Download Neuromuscular Blocking Agents

Neuromuscular Blocking Agents
François Donati
David R. Bevan
Key Points
•
Neuromuscular blocking agents are used to improve conditions for tracheal intubation, to
provide immobility during surgery, and to facilitate mechanical ventilation.
•
The main site of action of neuromuscular blocking agents (muscle relaxants) is on the nicotinic
cholinergic receptor at the endplate of muscle. They also have effects at presynaptic receptors
located on the nerve terminal.
•
Succinylcholine is a blocking agent that produces depolarization at the endplate and binds to
extrajunctional receptors. In spite of many side effects, such as hyperkalemia, its rapid offset
makes it the drug of choice for rapid sequence induction.
•
All other drugs available are nondepolarizing. They compete with acetylcholine for the same
binding sites.
•
Fade in response to high-frequency stimulation (e.g. train-of-four, 2 Hz for 2 seconds) is a
characteristic of nondepolarizing blockade. Train-of-four fade is difficult to evaluate manually or
visually during recovery when ratio is >0.4.
•
The upper airway is particularly sensitive to the effects of nondepolarizing blockade. Complete
recovery does not occur until train-of-four ratio at the adductor pollicis is >0.9.
•
Residual paralysis is more frequent with long-duration than intermediate-duration agents.
•
Reversal with anticholinesterases should be attempted when a certain degree of spontaneous
recovery is manifest. Ideally, all four twitches in response to train-of-four stimulation should be
visible before reversal is given.
•
After injection of the selective binding agent sugammadex, neuromuscular transmission is
restored because of 1:1 binding of sugammadex to rocuronium.
It appears paradoxical that drugs having peripheral effects on neuromuscular transmission might have a
role in anesthesia. If the patient is anesthetized, why provide agents to prevent movement? Yet, the
introduction of muscle relaxants, more appropriately called neuromuscular blocking agents, into clinical
practice in 1942 was an important milestone in the history of anesthesia.1 While the usefulness of the new
drugs became apparent, there were doubts regarding patient safety. In 1954, Beecher and Todd2 claimed
that anesthetic mortality increased sixfold when muscle relaxants were used. This situation was probably
because of the suboptimal use of mechanical ventilation and reversal drugs,
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but other controversies have arisen in recent years for a variety of reasons.
For example, the incidence of awareness appears to be greater when neuromuscular blocking agents are
used,3 and some authors recommend restricting the use of these drugs whenever possible, as patient
movement might be an indicator of consciousness. However, anesthetics act at the spinal cord level to
produce immobility; thus, movement in response to a noxious stimulus indicates inadequate analgesia and
does not necessarily mean the patient is conscious.4 Therefore, awareness does not occur because too
much neuromuscular blocking agent has been given, but because too little anesthetic is administered.
The controversy regarding neuromuscular blocking agents and awareness is complicated by the fact that
neuromuscular blockade seems to affect the bispectral index (BIS), which is the most widely used
measure of unconsciousness.5 Reductions in BIS have been reported in awake individuals receiving
succinylcholine and in mildly sedated patients given mivacurium.
Complete paralysis is not required for the duration of all surgical procedures. However, neuromuscular
blocking agents were found to make a difference in lower abdominal surgery, where surgical conditions
were better in patients receiving vecuronium (Fig. 20-1).6 In addition to providing immobility and better
surgical conditions, neuromuscular blocking agents improve intubating conditions. The doses of opioids
required for acceptable intubating conditions in the absence of muscle paralysis produce significant
hypotension (Fig. 20-2).7 Providing optimal intubating conditions is not a trivial objective. Poor intubating
conditions may increase the incidence of laryngeal injury, as manifested by voice hoarseness and vocal
cord damage (Fig. 20-3), and the best way to improve intubating conditions is to administer
neuromuscular blocking agents.8
It is also essential to make sure that the effects of neuromuscular blocking drugs have worn off or are
reversed before the patient regains consciousness. With the introduction of shorter-acting neuromuscular
blocking agents, many thought that reversal of blockade could be omitted. However, residual paralysis is
still a problem, nearly 30 years after if was first described (Table 20-1), and in spite of the availability of
shorter-acting neuromuscular blocking drugs and widespread use of neuromuscular monitoring.9 Part of
this might be related to the recognition that the threshold for complete neuromuscular recovery is a
train-of-four ratio of 0.9, instead of the traditional 0.7 (Fig. 20-4).132 Thus, an understanding of the
pharmacology of neuromuscular blocking agents and reversal drugs is essential.
Figure 20-1. Surgeon's assessment of muscle relaxation during
lower abdominal surgery. Rating goes from 1 (excellent) to 4
(poor). The incidence of poor rating was greater in patients not
given vecuronium (29%) compared with those who received the
drug (2%). (Redrawn from King M, Sujirattanawimol N,
Danielson DR, et al: Requirements for muscle relaxants during
View Figure
radical retropubic prostatectomy. Anesthesiology 2000; 93:
1392.)
Figure 20-2. Neuromuscular blocking agents provide better
intubating conditions than high doses of opioids, without
hypotension. Hypnotic agent was propofol or thiopental.
Intubating conditions are plotted against dose of remifentanil
(in micrograms per kilogram). Results for succinylcholine (Sux),
1 mg/kg (with little opioid) are given for comparison.
Hypotension was seen with remifentanil, 4 µg/kg.7 (Data
obtained from several different studies; references 7, 37, 38,
View Figure
69, 72, 159, and 160.)
Figure 20-3. Neuromuscular blocking agents improve
intubating conditions and reduce vocal cord sequelae. The
graph depicts the incidence of excellent and acceptable
(defined as good or excellent) intubating conditions after
atracurium or saline. The percentage of patients who reported
View Figure
hoarseness and those with vocal cord lesions documented by
stroboscopy is also shown. (Data from Mencke et al.8)
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Figure 20-4. Upper esophageal resting tone in
volunteers given vecuronium. Train-of-four ratio
(TOF) was measured at the adductor pollicis muscle.
Statistically significant decreases compared with
control were found at all levels of paralysis until TOF
>0.9. (Redrawn from Eriksson LI, Sundman E, Olsson
R, et al: Functional assessment of the pharynx at
rest and during swallowing in partially paralyzed
View Figure
humans: simultaneous videomanometry and
mechanomyography of awake human volunteers.
Anesthesiology 1997; 87: 1035.)
Table 20-1 Selected Reports of Residual Paralysis 1979–2007
RESID
UAL
PARAL
LONG-
YSIS
DURATION
TOF
(% OF
DRUGS
INTERMEDIATE-
REVER
THRES
PATIE
COMMENT
USED
DURATION DRUGS USED
SAL
HOLD
NTS)
S
—
Ye
0.7
42
—
STUDY
Viby
d-
-
Tuboc
Mog
urarin
ense
e
s
n et
Pancu
al.,13
roniu
8
m
1979
Galla
mine
Beva
Pancu
Ye
n et
roniu
s
al.,16
m
0.7
36
Less
paraly
sis
with
3
1988
Atracurium
Ye
0.7
4
s
atra
curiu
m and
vecur
onium
Vecuronium
Ye
0.7
9
0.7
12
s
Faw
Atracurium/vecur
Ye
cett
onium bolus
s
More
paraly
et
sis
al.,90
with
1995
infusi
ons
Atracurium/vecur
Ye
onium infusion
s
0.7
24
Berg
Pancu
Ye
et
roniu
s
al.,
m
0.7
26
More
atelec
tasis
1997
when
140
Atracurium/vecur
Ye
onium
s
0.7
5
resi
dual
paraly
sis
prese
nt
Bissi
Pancu
Ye
nger
roniu
s
et
m
0.7
20
More
hypoxi
a with
al.,16
4
2000
Vecuronium
Ye
0.7
8
s
TO
F<
0.7
Gatk
Rocuronium
Ye
e et
without
s
al.,12
AMG monitoring
0.8
17
Less
paraly
sis
1
when
2002
AMG
used
Rocuronium with
Ye
0.8
3
AMG monitoring
s
Deb
Atracurium/vecur
No
0.7
16
aene
onium/rocuroniu
sis
et
m
could
Paraly
al.,12
be
0
prese
2003
nt
even
0.9
45
4 hr
after
injecti
on
Mur
Pancu
No
0.8
82
After
phy
roniu
cardia
et
m
c
al.,66
surger
2003
y
when
Rocuronium
No
0.8
0
read
y to
wean
from
ventil
atory
suppo
rt
Mur
Pancu
Ye
phy
roniu
s
et
m
0.7
47
More
hypoxi
a and
al.,67
discha
2004
rge
0.9
97
dela
yed
with
pancu
roniu
m
Rocuronium
Ye
0.7
7
0.9
33
0.9
63
s
Baill
Atracurium/vecur
No
ard
onium/rocuroniu
(9
paraly
et
m
4%
sis
)
when
al.,14
Less
1
revers
2005
al and
monit
oring
used
Atracurium/vecur
No
onium/rocuroniu
(5
m
8%
0.9
3
)
AMG, acceleromyography; TOF, train-of-four ratio.
Physiology and Pharmacology
Structure
The cell bodies of motor neurons supplying skeletal muscle lie in the spinal cord. They receive and
integrate information from the central nervous system. This information is carried via an elongated
structure, the axon, to distant parts of the body. Each nerve cell supplies many muscle cells (or fibers) a
short distance after branching into nerve terminals. The terminal portion of the axon is a specialized
structure, the synapse, designed for the production and release of acetylcholine. The synapse is
separated from the endplate of the muscle fiber by a narrow gap, called the synaptic cleft, which is
approximately 50 nm in width (0.05 µm) (Fig. 20-5).11 The nerve terminal is surrounded by a Schwann cell,
and the synaptic cleft has a basement membrane and contains filaments that anchor the nerve terminal
to the muscle.
Figure 20-5. Schematic representation of the neuromuscular
junction (not drawn to scale).
View Figure
The endplate is a specialized portion of the membrane of the muscle fiber where nicotinic acetylcholine
receptors are concentrated. During development, multiple connections are made between nerve
terminals and a single muscle fiber. However, as maturation continues, most of these connections atrophy
and disappear, usually leaving only one connection per muscle fiber. This endplate continues to
differentiate from the rest of the muscle fiber. The nerve terminal enlarges, and folds appear. The
acetylcholine receptors cluster at the endplate, especially at the crests of the folds, and their density
decreases to almost zero in extrajunctional areas.12 Mammalian endplates usually have an oval shape with
the short axis perpendicular to the fiber. The width of the endplate is sometimes as large as the diameter
of the fiber, but is usually smaller. However, its length is only a small fraction of that of the fiber.
Nerve Stimulation
Under resting conditions, the electrical potential of the inside of a nerve cell is negative with respect to
the outside (typically -90 mV). If this potential is made less negative (depolarization), sodium channels
open and allow sodium ions to enter the cell. This influx of positive ions makes the potential inside the
membrane positive with respect to the outside. This potential change, in turn, causes depolarization of
the next segment of membrane, causing more sodium channels to open, and an electrical impulse, or
action potential, propagates. The duration of the action potential is brief (<1 msec) because of rapid
inactivation of sodium channels and activation of potassium channels. An action potential also triggers the
opening of calcium channels, allowing calcium ions to penetrate the cell. This entry of calcium facilitates
release of the neurotransmitter at the nerve terminal.
The sodium channels in the axon may be activated in response to electrical depolarization provided by a
nerve stimulator. A peripheral nerve is made up of a large number of axons, each of which responds in an
all-or-none fashion to the stimulus applied. Thus, in the absence of neuromuscular blocking agents, the
relationship between the amplitude of the muscle contraction and current applied is sigmoid. At low
currents, the depolarization is insufficient in all axons. As current increases, more and more axons are
depolarized to threshold and the strength of the muscle contraction increases. When the stimulating
current reaches a certain level, all axons are depolarized to threshold and
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propagate an action potential. Increasing current beyond this point does not increase the amplitude of
muscle contraction: the stimulation is supramaximal (Fig. 20-6). Most commercially available stimulators
deliver impulses lasting 0.1 to 0.2 msec.
Figure 20-6. Example of increasing stimulating current in one
patient. Current pulses, 0.2-msec duration, were delivered to
the ulnar nerve at the wrist every 10 seconds. The force of
contraction of the adductor pollicis muscle was measured and
appears as spikes. No twitch was seen if the current was <28
View Figure
mA. At current strengths of ≥40 mA, the current became
supramaximal; increasing the current produced little change in
force.
Release of Acetylcholine
Acetylcholine is synthesized from choline and acetate and packaged into 45-nm vesicles. Each vesicle
contains 5,000 to 10,000 acetylcholine molecules. Some of these vesicles cluster near the cell membrane
opposite the crests of the junctional folds of the endplate, in areas called active zones (Fig. 20-5).12
It is now widely accepted that acetylcholine is released in packets, or quanta, and that a quantum
represents the contents of one vesicle. In the absence of nerve stimulation, quanta are released
spontaneously, at random, and this is seen as small depolarizations of the endplate (miniature endplate
potential). When an action potential invades the nerve terminal, approximately 200 to 400 quanta are
released simultaneously, unloading approximately 1 to 4 million acetylcholine molecules into the synaptic
cleft.11 Calcium, which enters the nerve terminal through channels that open in response to
depolarization, is required for vesicle fusion and release. Calcium channels are located near docking
proteins, and this special geometric arrangement provides high intracellular concentrations of calcium to
allow binding of specialized proteins on the vesicle membrane with docking proteins.12 Binding produces
fusion of the membranes and release of acetylcholine ensues. When the calcium concentration is
decreased, or if the action of calcium is antagonized by magnesium, the release process is inhibited and
transmission failure may occur. Other proteins regulate storage and mobilization of acetylcholine vesicles.
It appears that a small proportion of vesicles is immediately releasable, while a much larger reserve pool
can be mobilized more slowly. Each impulse releases 0.2 to 0.5% of the 75,000 to 100,000 vesicles in the
nerve terminal. With repetitive stimulation, the amount of acetylcholine released decreases rapidly
because only a small fraction of the vesicles is in a position to be released immediately. To sustain
release during high-frequency stimulation, vesicles must be mobilized from the reserve pool.
Postsynaptic Events
The 1 to 10 million receptors located at the endplate bind to acetylcholine as the physiological ligand,
and belong to the class of nicotinic receptors. Cholinergic nicotinic receptors respond to acetylcholine
and other agonists by allowing passage of ions. Nicotinic receptors are made up of five glycoprotein
subunits arranged in the form of a rosette and lying across the whole cell membrane (Fig. 20-7). The
nicotinic subtype present at the neuromuscular junction is made up of two identical subunits, designated
α, and three others, called β, δ, and γ or ε. There are two acetylcholine binding sites, each located on
the outside part of the α subunit. When two acetylcholine molecules bind simultaneously to each binding
site, an opening is created in the center of the rosette, allowing sodium ions to enter the cell and
potassium ions to exit.11,12 The inward movement of sodium is predominant because it is attracted by the
negative voltage of the inside of the cell. This movement of sodium depolarizes the endplate; that is, its
inside becomes less negative. There is a high density of sodium channels in the folds of synaptic clefts and
in the perijunctional area.12,13 These channels open when the membrane is depolarized beyond a critical
point, allowing more sodium to enter the cell and producing further depolarization. This depolarization
generates an action potential, which propagates by activation of sodium channels along the whole length
of the muscle fiber. The muscle action potential has a duration of 5 to 15 msec and can be recorded as an
electromyogram (EMG). It precedes the onset of contraction, or twitch, which lasts 100 to 200 msec. With
high-frequency (>10 Hz) stimulation, the muscle fiber does not have time to relax before the next
impulse, so contractions fuse and add up, and a tetanus is obtained.
There are two types of nicotinic acetylcholine receptors. Early in development, receptors are evenly
distributed along the whole length of the muscle fiber. These receptors, called fetal receptors, have a γ
subunit (Fig. 20-7). When the endplate develops, receptors tend to cluster at the neuromuscular junction
and leave only few receptors in the extrajunctional areas. As maturation continues, the γ subunit is
substituted by an ε subunit, which is characteristic of the adult type, junctional receptor.12 In humans,
the switch occurs in the third trimester of pregnancy. Maintenance of adult receptors at the endplate
depends on the integrity of nerve supply. A few γ-type, extrajunctional receptors still persist in adults
and can proliferate in cases of denervation. Both types of receptor have
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two binding sites for acetylcholine, located on each of the α subunits, but they have slightly different
sensitivities to agonist and antagonist drugs.12
Figure 20-7. There are two types of nicotinic receptors in
muscle. Both have the same five subunits, except for a
substitution of the ε for the γ subunits. The acetylcholine
binding sites are represented by a shaded oval area. They are
on the α subunit, at the δ and ε or γ interface, respectively.
View Figure
According to some authors, the order of the β and δ is
inverted.
The main action of nondepolarizing neuromuscular blocking drugs is to bind to at least one of the two α
subunits of the postsynaptic receptor. This prevents access to the receptor by acetylcholine and does not
produce opening of the receptor. Under normal circumstances, only a small fraction of available
receptors must bind to acetylcholine to produce sufficient depolarization to trigger a muscle contraction.
In other words, there is a wide “margin of safety.”13 This redundancy implies that neuromuscular
blocking drugs must be bound to a large number of receptors before any blockade is detectable. Animal
studies suggest that 75% of receptors must be occupied before twitch height decreases in the presence of
d-tubocurarine, and blockade is complete when 92% of receptors are occupied.14 The actual number
depends on species and type of muscle, and humans might have a reduced margin of safety compared
with other species.13 So it is futile to correlate receptor occupancy data obtained in cats with certain
clinical tests in humans, such as hand grip and head lift, which involve different muscle groups. However,
the general concept that a large proportion of receptors must be occupied before blockade becomes
detectable, and that measurable blockade occurs over a narrow range of receptor occupancy, remains
applicable to clinical practice. Because it must overcome the margin of safety, the initial dose of
neuromuscular blocking agent is greater than maintenance doses.
Acetylcholine is hydrolyzed rapidly by the enzyme acetyl cholinesterase, which is present in the folds of
the endplate as well as embedded in the basement membrane of the synaptic cleft. The presence of the
enzyme in the synaptic cleft suggests that not all the acetylcholine released reaches the endplate; some
is hydrolyzed en route.12,15
Presynaptic Events
The release of acetylcholine normally decreases during high-frequency stimulation because the pool of
readily releasable acetylcholine becomes depleted faster than it can be replenished. Under normal
circumstances, the reduced amount released is well above what is required to produce muscle
contraction because of the high margin of safety at the neuromuscular junction. In addition, a positive
feedback system involving activation of presynaptic receptors helps in the mobilization of acetylcholine
vesicles. Although studies aimed at identifying these receptors are extremely difficult to perform, there is
some evidence that there the presynaptic and postsynaptic receptors are of different subtypes.
Presynaptic receptors are most likely of the α3β2 subtype, that is they are made up of only α and β
subunits.16,17 Both the α subunits are slightly different from those found in postsynaptic receptors (thus the
designation as α3, instead of the α1 given to postsynaptic receptors). The other three subunits are all
identical (β2), and slightly different from the β1 subunit found in postsynaptic receptors.
The physiological role of the presynaptic receptors is to maintain the number of vesicles ready to be
released. Nondepolarizing neuromuscular blocking drugs produce characteristic TOF and tetanic fade,
probably by blocking presynaptic nicotinic receptors,16 thus preventing mobilization of acetylcholine
vesicles and leading to reduced acetylcholine release during high-frequency stimulation. Succinylcholine
has virtually no effect on these presynaptic receptors, which would explain the lack of fade observed with
this drug.17 Fade constitutes a key property of nondepolarizing neuromuscular blocking drugs and is
useful for monitoring purposes.
Neuromuscular Blocking Agents
Neuromuscular blocking drugs interact with the acetylcholine receptor either by depolarizing the
endplate (depolarizing agents) or by competing with acetylcholine for binding sites (nondepolarizing
agents). The only depolarizing agent still in use is succinylcholine. All others are of the nondepolarizing
type.
Pharmacologic Characteristics of Neuromuscular Blocking
Agents
The effect of neuromuscular blocking drugs is measured as the depression of adductor muscle
contraction (twitch) following electrical stimulation of the ulnar nerve. The value is compared with a
control value, obtained before injection of the drug. Each drug has characteristic onset, potency,
duration of action, and recovery index.
Potency of each drug is determined by constructing dose-response curves, which describe the relationship
between twitch depression and dose (Fig. 20-8).18 Then, the effective dose 50, or ED50, which is the
median dose corresponding to 50% twitch depression, is obtained. Because clinically useful relaxation is
attained when twitch is abolished almost completely, the ED95, corresponding to 95% block, is more
commonly used. For example, the ED95 for vecuronium is 0.05 mg/kg, which means that half the patients
will achieve at least 95% block of single twitch (compared with the prevecuronium value) with that dose,
and half the subjects will reach <95% block. Rocuronium has an ED95 of 0.3 mg/kg. Therefore, it has onesixth the potency of vecuronium. In other words, compared with vecuronium, 6 times as much rocuronium
has to be given to produce the same effect. The ED95 of known neuromuscular blocking agents vary over
two orders of magnitude (Table 20-2).
Onset time, or time to maximum blockade, can be shortened if the dose is increased. When two or more
drugs are
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compared, it is meaningful to compare only equipotent doses and usually clinically relevant doses (2 ×
ED95) are considered.18
Figure 20-8. Example of a dose-response relationship. The
actual numbers are approximately those for rocuronium. The
ED50 is the dose corresponding to 50% blockade and ED95 is the
dose corresponding to 95% blockade.
View Figure
Duration of action is the time from injection of the neuromuscular blocking agent to return of 25%
twitch height (compared with control). Duration increases with dose, so comparisons are normally made
with 2 × ED95 doses. The 25% twitch height figure was chosen because rapid reversal can normally be
achieved at that level. Categories were proposed for neuromuscular blocking drugs according to their
duration of action (Table 20-2).18 Same duration agents may have markedly different onsets.
Table 20-2 Potency, Onset Time, Duration, and Recovery Index of Neuromuscular
Blocking Agentsa
AGENT
ED95 (mg/kg)
ONSET TIME
DURATION TO 25%
RECOVERY INDEX (25–75%
(min)
RECOVERY (min)
RECOVERY) (min)
ULTRASHORT-DURATION AGENTS
Succinylcholine
0.3
1–1.5
6–8
2–4
Gantacuriumb
0.19
1.7
6–8
2.5
SHORT-DURATION AGENTS
Mivacuriumc
0.08
3–4
15–20
7–10
Rapacuroniumc
0.75
1–1.5
15–25
5–7
INTERMEDIATE-DURATION AGENTS
Atracurium
0.2–0.25
3–4
35–45
10–15
Cisatracurium
0.05
5–7
35–45
12–15
Rocuronium
0.3
1.5–3
30–40
8–12
Vecuronium
0.05
3–4
35–45
10–15
0.25
3–5
60–90
30–40
LONG-DURATION AGENTS
Alcuroniumc
Doxacurium
0.025
5–10
40–120
30–40
d-Tubocurarinec
0.5
2–4
60–120
30–45
Gallaminec
2
1.5–3
60–120
30–60
Metocurinec
0.3
3–5
60–150
40–60
Pancuronium
0.07
2–4
60–120
30–40
Pipecuroniumc
0.05
3–5
90–130
35–45
a
Typical values for the average young adult patient. Onset and duration data depend on dose. The
values presented are the best estimates available for twice the ED95 and are measured at the
adductor pollicis muscle with nitrous oxide and no volatile agent. Actual values may vary markedly
from one individual to the next, and may be affected by age, other medications, and/or disease
states. The categories under which the drugs are classified are somewhat arbitrary.
Being investigated at the time of writing.
b
c
No longer used or very limited use in North America.
Recovery index is the time interval between 25% and 75% twitch height. It provides information about the
speed of recovery once return of twitch is manifest. Contrary to duration of action, it does not depend
heavily on the dose given. The values for ED95, onset time, duration of action, and recovery index depend
on which muscle is used to make measurements. For consistency, the adductor pollicis muscle has been
retained as the gold standard, not because of its physiological significance but because it is most
commonly monitored and data on it are most abundant.
The pharmacologic characteristics of neuromuscular blocking agents are completed by an assessment of
intubating conditions, which do not always parallel twitch height at the adductor pollicis muscle.
Intubating conditions depend on paralysis of centrally located muscles, but also on the type and quantity
of opioid and hypnotic drugs given for induction of anesthesia. To decrease variability between studies,
criteria to grade intubating conditions as excellent, good, poor, or impossible in a scoring system were
adopted by a group of experts who met in Copenhagen in 1994.19
Depolarizing Drugs: Succinylcholine
Among drugs that depolarize the endplate, only succinylcholine is still used clinically. In spite of a long
list of undesired effects, succinylcholine remains popular because it is the only ultrarapid
onset/ultrashort duration neuromuscular blocking drug currently available.
Neuromuscular Effects
The effects of succinylcholine at the neuromuscular junction are not completely understood. The drug
depolarizes postsynaptic and extrajunctional receptors. However, when the receptor is in contact with
any agonist, including acetylcholine, for a prolonged time it ceases to respond to the agonist. Normally,
this desensitization process does not occur with acetylcholine because of its rapid breakdown (<1 msec).
However, succinylcholine remains at the endplate for much longer, so desensitization develops after a
brief period of activation.17 Another possible mechanism is the inactivation of sodium channels in the
junctional and perijunctional areas, which occurs when the membrane remains depolarized.17 This
inactivation prevents the propagation of the action potential. Both desensitization of the receptor and
inactivation of sodium channels might be present together.
Within 1 minute after succinylcholine injection and before paralysis is manifest, some disorganized
muscular activity is frequently observed. This phenomenon is called fasciculation.
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This activity probably reflects the agonist effect of succinylcholine, before desensitization takes place.
Small doses of nondepolarizing drugs are effective in reducing the incidence of fasciculations.20
Succinylcholine has yet another neuromuscular effect. In some muscles, like the masseter and to a lesser
extent the adductor pollicis, a sustained increase in tension that may last for several minutes can be
observed. The mechanism of action of this tension change is uncertain but is most likely mediated by
acetylcholine receptors because it is blocked by large amounts of nondepolarizing drugs.21 The increase in
masseteric tone, which is probably always present to some degree but greater in some susceptible
individuals, may lead to imperfect intubating conditions in a small proportion of patients. Masseter
muscle spasm may be an exaggerated form of this response.
Characteristics of Depolarizing Blockade
After injection of succinylcholine, single-twitch height is decreased. However, the response to highfrequency stimulation is sustained: minimal train-of-four and tetanic fade is observed. The block is
antagonized by nondepolarizing agents so that the ED95 is increased by a factor two if a small dose of
nondepolarizing drug is given before.22 Succinylcholine blockade is potentiated by inhibitors of acetyl
cholinesterase, such as neostigmine and edrophonium.23
Phase II Block
After administration of 7 to 10 mg/kg, or 30 to 60 minutes of exposure to succinylcholine, train-of-four
and tetanic fade become apparent. Neostigmine or edrophonium can antagonize this block, which has
been termed nondepolarizing, dual, or phase II block. The onset of phase II block coincides with
tachyphylaxis, as more succinylcholine is required for the same effect.
Pharmacology of Succinylcholine
Succinylcholine is rapidly hydrolyzed by plasma cholinesterase (also called pseudocholinesterase), with an
elimination half-life of <1 minute in patients.24 Because of the rapid disappearance of succinylcholine
from plasma, the maximum effect is reached quickly. Subparalyzing doses (up to 0.3 to 0.5 mg/kg) reach
their maximal effect within approximately 1.5 to 2 minutes at the adductor pollicis muscle,22 and within 1
minute at more central muscles, such as the masseter, the diaphragm, and the laryngeal muscles. With
larger doses (1 to 2 mg/kg), abolition of twitch response can be reached even more rapidly.
The mean dose producing 95% blockade (ED95) at the adductor pollicis muscle is 0.30 to 0.35 mg/kg with
opioid–nitrous oxide anesthesia.22 In the absence of nitrous oxide, the ED95 is increased to 0.5 mg/kg.25
These values are doubled if d-tubocurarine, 0.05 mg/kg, is given as a defasciculating agent.22 The time
until full recovery is dose-dependent and reaches 10 to 12 minutes after a dose of 1 mg/kg.
Side Effects
Cardiovascular
Sinus bradycardia with nodal or ventricular escape beats (or both) may occur, especially in children, and
asystole has been described after a second dose of succinylcholine in both pediatric and adult patients.
These effects can be attenuated with atropine or glycopyrrolate.26 The mechanisms for the cardiovascular
side effects of succinylcholine are not known because succinylcholine appears to have little effect of
autonomic cholinergic receptors.17 Succinylcholine increases catecholamine release, and tachycardia is
seen frequently.
Anaphylaxis
Succinylcholine has been incriminated as the trigger of allergic reactions more often than any other drug
used in anesthesia. Successive studies conducted in France indicate that the number of reported events is
decreasing, corresponding to the gradual replacement of succinylcholine by nondepolarizing drugs.27 The
incidence of anaphylactic reactions to succinylcholine is difficult to establish, but is probably of the order
of 1:5,000 to 1:10,000.
Fasciculations
The prevalence of fasciculations is high (60 to 90%) after the rapid injection of succinylcholine, especially
in muscular adults. Fasciculations are a benign side effect of the drug, but many clinicians prefer to
prevent fasciculations. In this respect, a small dose of a nondepolarizing neuromuscular blocking drug is
given 3 to 5 minutes before succinylcholine is effective.20 When the drug was available, d-tubocurarine
0.05 mg/kg was used for this purpose. Rocuronium is an acceptable alternative, as long as appropriate
doses (0.03 to 0.04 mg/kg, or 10% of the ED95) are given.28 In one study, rocuronium, 0.03 mg/kg,
decreased the incidence of fasciculations from 90 to 10%.29 A dose of 0.06 mg/kg leads to an unacceptably
high incidence of symptoms of neuromuscular weakness, such as blurred vision, heavy eyelids, voice
changes, difficulty swallowing, or even dyspnea, in the awake patient.30 A recent meta-analysis shows that
these side effects have been observed frequently in studies of defasciculating doses of neuromuscular
blocking agents,20 but these side effects are most likely related to the high dose given.28 Atracurium, 0.02
mg/kg, is also effective. Pancuronium, vecuronium, cisatracurium, and mivacurium are not as effective as
defasciculants. After these nondepolarizing drugs, the dose of succinylcholine must be increased from 1
mg/kg to 1.5 or even 2 mg/kg because of the antagonism between depolarizing and nondepolarizing
drugs.22 Other drugs, such as diazepam, lidocaine, fentanyl, calcium, vitamin C, magnesium, and
dantrolene, have all been used to prevent fasciculations. The results are no better than with
nondepolarizing relaxants and they may have undesirable effects of their own. The administration of
small (10-mg) doses of succinylcholine 1 minute before the intubating dose, does not appear to be
effective29 and has largely been abandoned.
Muscle Pains
Generalized aches and pains, similar to the myalgia that follows violent exercise, are common 24 to 48
hours after succinylcholine administration. Their incidence is variable (1.5 to 89% of patients receiving
succinylcholine) and are more common in young, ambulatory patients.31 The intensity of muscle pains is
not always correlated with the intensity of fasciculations, but the methods that have been shown
effective to prevent fasciculations usually prevent muscle pains. For example, a precurarization dose of a
nondepolarizing neuromuscular blocking agent is effective. Lidocaine (1 to 1.5 mg/kg), especially in
conjunction with precurarization, has also been shown to be of value.31 Calcium, vitamin C,
benzodiazepines, magnesium, and dantrolene have been tried with inconclusive results.31
Intragastric Pressure
Succinylcholine increases intragastric pressure, and this effect is blocked by precurarization. However,
succinylcholine
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causes even greater increases in lower esophageal sphincter pressure. Thus, succinylcholine does not
appear to increase the risk of aspiration of gastric contents unless the lower esophageal sphincter is
incompetent.
Intraocular Pressure
Intraocular pressure increases by 5 to 15 mm Hg after injection of succinylcholine. The mechanism is
unknown but occurs after detachment of extraocular muscle, suggesting an intraocular etiology.
Precurarization with a nondepolarizing blocker has little or no effect on this increase. This information
has led to the widespread recommendation to avoid succinylcholine in open-eye injuries. However, it
must be appreciated that inadequate anesthesia, elevated systemic blood pressure, and insufficient
neuromuscular blockade during laryngoscopy and tracheal intubation might increase intraocular pressure
more than succinylcholine. In addition, there is little evidence that the use of succinylcholine has led to
blindness or extrusion of eye content.32
Intracranial Pressure
Succinylcholine may increase intracranial pressure, and this response is probably diminished by
precurarization.33 Again, laryngoscopy and tracheal intubation with inadequate anesthesia or muscle
relaxation are likely to increase intracranial pressure even more than succinylcholine.
Hyperkalemia
Serum potassium increases by approximately 0.5 mEq/L after injection of succinylcholine. This increase is
not prevented completely by precurarization. In fact, only large doses of nondepolarizing blockers reliably
abolish this effect.34 Subjects with pre-existing hyperkalemia, such as patients in renal failure, do not
have a greater increase in potassium levels, but the absolute level might reach the toxic range.
Succinylcholine is safe in normokalemic renal-failure patients.35 Severe hyperkalemia, occasionally leading
to cardiac arrest, has been described in patients after major denervation injuries, spinal cord transection,
peripheral denervation, stroke, trauma, extensive burns, and prolonged immobility with disease, and may
be related to potassium loss via a proliferation of extrajunctional receptors.34 Hyperkalemia has been
reported with myotonia and muscle dystrophies, and cardiac arrests have been reported in children
before the diagnosis of the disease was made.34 Severe hyperkalemia after succinylcholine resulting in
cardiac arrest has also been observed in acidotic hypovolemic patients.
Abnormal Plasma Cholinesterase
Plasma cholinesterase activity can be reduced by a number of endogenous and exogenous causes, such as
pregnancy, liver disease, uremia, malnutrition, burns, plasmapheresis, and oral contraceptives. These
conditions usually lead to a slight, clinically unimportant increase in the duration of action of
succinylcholine.36 Plasma cholinesterase activity is reduced by some anticholinesterases (e.g.,
neostigmine) so that the duration of succinylcholine given after neostigmine, but not after edrophonium,
is increased.23
A small proportion of patients have a genetically determined inability to metabolize succinylcholine.
Either plasma cholinesterase is absent or an abnormal form of the enzyme is present. Only patients
homozygous for the condition (approximately 1:2,000 individuals) have prolonged paralysis (3 to 6 hours)
after usual doses of succinylcholine (1 to 1.5 mg/kg). In heterozygous patients (1:30 cases), the duration
of action is only slightly prolonged compared with normal individuals. Traditional methods for identifying
plasma cholinesterase phenotype involve measurement of enzyme activity with a substrate and inhibition
with dibucaine, fluoride, and chloride. These tests are only capable of identifying some enzyme variants.
The complete amino acid sequence of plasma cholinesterase has now been determined using molecular
genetics techniques. The cholinesterase gene is located on chromosome 3 at q26,36 and over 20 mutations
in the coding region of the plasma cholinergic gene have been identified. Whole blood or fresh-frozen
plasma can accelerate succinylcholine metabolism in patients with low or absent plasma cholinesterase,
but the best course of action is probably mechanical ventilation of the lungs until full recovery of
neuromuscular function can be demonstrated. Neostigmine and edrophonium are unpredictable in the
reversal of abnormally prolonged succinylcholine blockade and are best avoided.
Clinical Uses
The main indication for succinylcholine is to facilitate tracheal intubation. In adults, a dose of 1.0 mg/kg
yields 75 to 80% excellent intubation conditions within 1 to 1.5 minutes after an induction sequence that
includes a hypnotic (propofol or thiopental) and a moderate opioid dose.37,38 The dose must be increased
to 1.5 to 2.0 mg/kg if a precurarizing dose of nondepolarizing blocker has been used.22 Intubating
conditions without precurarization are only marginally improved by increasing the dose to 2 mg/kg.38
Succinylcholine is especially indicated for “rapid sequence induction,” when a patient presents with a full
stomach and the possibility of aspiration of gastric contents. In this situation, manual ventilation of the
lungs is avoided, if possible, to reduce the probability of aspiration because of excessive intragastric
pressure caused by gas forced via face mask. Thus, the ideal neuromuscular blocking agent has both a
fast onset, to reduce the time between induction and intubation of the airway, and a rapid recovery, to
allow return of normal breathing before the patient becomes hypoxic. The duration of action of
succinylcholine, given at a dose of 1 mg/kg, is short enough so that in the majority of properly
preoxygenated patients resume respiratory efforts (5 to 6 minutes) before hypoxia can be detected.39 It
has been argued that this is valid only in relatively healthy subjects and not in all cases. As a result, a
lower dose has been suggested. However, a dose of 0.5 to 0.6 mg/kg results in substantially fewer
patients with excellent intubating conditions, and the decrease in duration is modest.37,38 For maintenance
of relaxation, typical infusion rates are approximately 50 to 100 µg/kg/min. However, the availability of
short and intermediate nondepolarizing drugs makes succinylcholine infusions obsolete.
Children are slightly more resistant to succinylcholine than adults,40 and doses of 1 to 2 mg/kg are
required to facilitate intubation. In infants, 2 to 3 mg/kg may be required. Precurarization is not
necessary in patients younger than 10 years because fasciculations are uncommon in this age group.
Bradycardia is common in children unless atropine or glycopyrrolate is given.26 Succinylcholine, at a dose
of 4 mg/kg, is the only effective intramuscular neuromuscular blocking agent in children with difficult
intravenous access and provides adequate intubating conditions in about 4 minutes. However, this route
of administration should not be the method of choice.41
In obese individuals, the dose of succinylcholine, in milligrams per kilogram of actual body weight, is the
same as in leaner patients. Calculating the dose per kilogram ideal body weight might lead to underdosing
and inadequate intubating conditions.42 The volume of distribution, expressed per kilogram of actual body
weight, of succinylcholine is probably
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decreased in obese individuals, but this is compensated by an increase in plasma cholinesterase activity.
Nondepolarizing Drugs
Nondepolarizing neuromuscular blocking drugs bind to the postsynaptic receptor in a competitive
fashion, by binding to one of the α subunits of the receptor (Fig. 20-7).12
Characteristics of Nondepolarizing Blockade
The fade observed in response to high-frequency stimulation (>0.1 Hz) is characteristic of nondepolarizing
blockade.16 With EMG recordings, fade is relatively constant in the range 2 to 50 Hz.43 Mechanical fade is
greater with 100 Hz than with 50 Hz.44 Tetanic stimulation is followed by posttetanic facilitation, which is
an increased response to any stimulation applied soon after the tetanus. The intensity and duration of this
effect depend on the frequency and duration of the tetanic stimulation. With a 50-Hz tetanus of 5-second
duration, twitch responses have been found to fall within 10% of their pretetanic values in 1 to 2 minutes45
(Fig. 20-9).
Finally, nondepolarizing blockade can be antagonized with anticholinesterase agents such as
edrophonium, neostigmine, or pyridostigmine. It is also antagonized by depolarizing agents such as
succinylcholine provided that the nondepolarizing blockade is intense and that the succinylcholine dose is
too small to produce a block of its own.
Pharmacokinetics
As is the case for other drugs used in anesthesia, the elimination half-life of neuromuscular blocking
agents does not always correlate with duration of action because termination of action sometimes
depends on redistribution instead of elimination. However, knowledge of the kinetics of the drug helps us
understand the behavior of the drug in special situations (prolonged administration, disease of the organs
of elimination, and so on).
Several mechanisms can explain the various categories of durations of action listed in Table 20-3:
•
All long-duration drugs all have a long (1 to 2 hours) elimination half-life and depend on liver
and/or kidney function for termination of action.
Figure 20-9. Characteristics of nondepolarizing
blockade. Train-of-four responses are equal before
administration of vecuronium (arrow). For a given
twitch depression, fade is less during onset (top trace)
View Figure
than recovery (bottom trace). A 50-Hz tetanus was
applied during recovery. Tetanic fade is seen with
posttetanic facilitation, that is a greater train-of-four
response after than before the train.
•
Intermediate-duration drugs either have an intermediate elimination half-life (atracurium and
cisatracurium) or they have long elimination half-lives (1 to 2 hours) but depend on redistribution
rather than elimination for termination of effect (vecuronium and rocuronium; Fig. 20-10).
•
Short-duration drugs have either short elimination half-lives (the active isomers of mivacurium)
or long elimination half-life but extensive redistribution (rapacuronium).
•
Ultrashort-duration drugs have a very short elimination half-life (succinylcholine).
The volume of distribution of all these agents is approximately equal to extracellular fluid (ECF) volume
(0.2 to 0.4 L/kg; Table 20-3). In infants, in whom the ECF volume as a proportion of body weight, is
increased, the volume of distribution of neuromuscular blocking drugs parallels ECF volume closely.
Onset and Duration of Action
Onset time of neuromuscular blocking drugs is determined by the time required for drug concentrations
at the site of action to reach a critical level, usually that corresponding to 100% block. Onset time (2 to 7
minutes) is longer than time to peak plasma concentrations (<1 minute). This delay reflects the time
required for drug transfer between plasma and neuromuscular junction and is represented quantitatively
by a rate constant (keo). This rate constant corresponds to half-times of 5 to 10 minutes for most
nondepolarizing drugs and is determined by all the factors that modify access of the drug to, and its
removal from, the neuromuscular junction. These include cardiac output, distance of the muscle from
the heart, and muscle blood flow. Thus, onset times are not the same in all muscles because of different
blood flows. Also, if metabolism or redistribution is very rapid, for example, in the case of
succinylcholine, the onset time is accelerated. Finally, potent drugs have a slower onset of action than
less potent agents (Fig. 20-11).46 This is because a large proportion of receptors must be occupied before
blockade can be observed. Blockade of these receptors will occur faster, and onset will be more rapid, if
more drug molecules are available, that is, if potency is low. Table 20-2 shows that onset tends to be
slower if a drug is potent, that is, if ED95 is small.
Duration of action is determined by the time required for drug concentrations at the site of action to
decrease below a certain level, usually corresponding to 25% first twitch blockade. Duration is determined
chiefly by plasma concentrations, at least for intermediate- and long-duration drugs.
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Figure 20-10. Concentrations at the neuromuscular junction
for six representative drugs, after bolus doses of 2 × ED95.
Concentrations at the neuromuscular junction lag somewhat
behind plasma concentrations. The level corresponding to 25%
recovery is indicated. The curves were moved up or down so
View Figure
that the 25% level matched. Succinylcholine and the active
mivacurium isomers have a rapid elimination. Pancuronium has
a long half-life and recovery occurs during the elimination
phase. Cisatracurium has an intermediate terminal half-life,
and recovery also occurs during the elimination phase.
Rocuronium and vecuronium have an elimination half-life
comparable with that of pancuronium. However, an important
redistribution occurs before, and 25% recovery occurs during
that redistribution process. As a result, both rocuronium and
vecuronium have a duration of action comparable with that of
cisatracurium.
Figure 20-11. Neuromuscular blockade as a function of time
for four neuromuscular blocking agents. Onset is faster for
the less potent succinylcholine and rocuronium than for the
more potent vecuronium and cisatracurium. (From Kopman AF,
Klewicka MM, Kopman DJ, et al: Molar potency is predictive of
the speed of onset of neuromuscular block for agents of
View Figure
intermediate, short, and ultrashort duration. Anesthesiology
1999; 90: 425, with permission.)
Table 20-3 Typical Pharmacokinetic Data for Neuromuscular Blocking Agents in Adults,
Except where Stated
VOLUME OF DISTRIBUTION
CLEARANCE
ELIMINATION HALF-LIFE
(L/kg)
(mL/kg/min)
(min)
DRUG
ULTRASHORT-DURATION AGENTS
Succinylcholine
0.04
37
0.65
Trans–trans
0.05
29
2.4
Cis–trans
0.05
46
2.0
Cis–cis
0.18
7
30
SHORT-DURATION AGENTS
Mivacurium
Rapacuronium
0.2
7
100
0.14
5.5
20
Adults
0.12
5
23
Intensive care
0.26
6.5
25
Adults
0.3
3
90
Intensive care
0.7
3
330
0.4
5
70
0.2
2.5
95
Adults
0.3
1–3
90
Elderly
0.3
0.8
270
INTERMEDIATE-DURATION AGENTS
Atracurium
Cisatracurium
Rocuronium
Vecuronium
LONG-DURATION AGENTS
Doxacurium
d-Tubocurarine
Neonates
0.7
1.1
300
Infants
0.5
1.0
300
Children
0.3
1.5
90
0.3
1.8
140
Pancuronium
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Individual Nondepolarizing Agents
Since 1942, nearly 50 nondepolarizing neuromuscular blocking agents have been introduced into clinical
anesthesia. This section covers only those drugs currently available in North America and Europe, plus a
few others of historical interest. The first agent to undergo clinical investigation was Intocostrin, or dtubocurarine, the purified and standardized product of curare obtained from the plant Chondodendrom
tomentosum.1 d-Tubocurarine has been completely replaced by more modern synthetic analogues.
d-Tubocurarine
The dose of d-tubocurarine required to produce 95% twitch block of at the adductor pollicis muscle, or
ED95, is 0.5 mg/kg. At that dose, the duration of action is typical of a long-duration agent (Table 20-2).47
Pharmacology
The molecule undergoes minimal metabolism so that 24 hours after its administration about 10% of the
compound is found in the urine and 45% in the bile. Like most other neuromuscular blocking drugs, it is
not extensively (30 to 50%) protein bound. Excretion is impaired in renal failure.
Cardiovascular Effects
Hypotension frequently accompanies the administration of d-tubocurarine even at doses <ED95. The
mechanism involved is mainly histamine release, and skin flushing is frequently observed. Autonomic
ganglionic blockade may also play a minor role.
Age
Pharmacokinetic studies have been performed in all age groups, and the results are helpful in
understanding the behavior of all nondepolarizing agents in patients at the extremes of age. The potency
of d-tubocurarine on a milligram per kilogram basis does not vary greatly with age. Infants demonstrate
greater blockade than older children or adults if the same concentration of d-tubocurarine is applied.
However, infants have an increased volume of distribution, when expressed in milliliters per kilogram of
body weight, so that the same milligram per kilogram dose produces a reduced concentration. The net
effet is similar blockade after a given milligram per kilogram dose in infants, older children, and adults
(Table 20-3).48 This phenomenon has also been observed with other neuromuscular blocking agents.
However, the decreased glomerular filtration rate in the very young and the very old results in an
increased elimination half-life and prolonged duration of action.48 The onset of action is more rapid in the
young as a result of a more rapid circulation time.
Burns
Patients with massive burns demonstrate resistance to d-tubocurarine and other nondepolarizing drugs
that depends on the size of the burn and the time since injury.49 Higher concentrations of the free drug
are required to produce a given degree of twitch depression compared with nonthermally injured
patients. Compared with normal subjects, the number of acetylcholine receptors is increased in muscles
close to the site of burn injury, but also, to a lesser extent, in more distant muscles.50
Clinical Use
The long duration and cardiovascular effects of d-tubocurarine have restricted its use and constituted a
stimulus for the production of alternative agents. Initially, this led to the introduction of pancuronium,
which replaced the hypotension of d-tubocurarine with hypertension and tachycardia. More recently,
drugs of intermediate duration (atracurium, cisatracurium, vecuronium, and rocuronium) with virtually no
cardiovascular effects have almost eliminated the use of d-tubocurarine. When available, d-tubocurarine
has been mainly confined to be used as a “precurarization” (3 mg/70 kg) before succinylcholine to reduce
fasciculations and muscle pains. Rocuronium has largely replaced d-tubocurarine for this indication.
Alcuronium
Although it has never been available in North America, alcuronium still enjoys limited use in some
countries. The ED95 is approximately 0.2 to 0.25 mg/kg. Intubating doses are usually limited to 0.3 mg/kg
because of the long duration of action. Although it was introduced as an intermediate-duration drug, its
recovery index (37 minutes) makes it a long-acting neuromuscular blocking agent.51
Atracurium
Atracurium is a bisquaternary ammonium benzylisoquinoline compound of intermediate duration of
action. It is degraded via two metabolic pathways. One of these pathways is the Hofmann reaction, a
nonenzymatic degradation with a rate that increases as temperature and/or pH increases. The second
pathway is nonspecific ester hydrolysis. The enzymes involved in this metabolic pathway are a group of
tissue esterases, which are distinct from plasma or acetyl cholinesterases.52 The same group of enzymes is
involved in the degradation of esmolol and remifentanil. It has been estimated that two thirds of
atracurium is degraded by ester hydrolysis and one third by Hofmann reaction. Subjects with abnormal
plasma cholinesterase have a normal response to atracurium.
The end products of the degradation of atracurium are laudanosine and acrylate fragments. Laudanosine
has been reported as causing seizures in animals, but at doses largely exceeding the clinical range. No
deleterious effect of laudanosine has been demonstrated conclusively in humans.52 Laudanosine is
excreted by the kidney. Acrylates have been shown to inhibit human cell proliferation in vitro.53 However,
the concentrations and exposure times required to obtain this effect are much greater than what is
obtained normally in clinical practice.
Pharmacology
Atracurium is an intermediate-duration drug, with a terminal half-life of approximately 20 minutes.
Termination of effect occurs during the elimination phase of the drug. Duration of action does not depend
on age, renal function, or hepatic function.
The ED95 of atracurium is 0.2 to 0.25 mg/kg. The onset of action (3 to 5 minutes at 2 × ED95) of equipotent
doses is similar for atracurium, pancuronium, d-tubocurarine, and vecuronium. It is slower than
succinylcholine. As with any neuromuscular blocking agent, onset of atracurium can be shortened if the
dose is increased, but it is not recommended to exceed 0.5 mg/kg because of hypotension and histamine
release. The duration of action is also dose-related. The time to 25% first twitch recovery after 0.5 mg/kg
is approximately 30 to 40 minutes.
Cardiovascular Effects
Like d-tubocurarine, atracurium releases histamine in a dose-related manner. If large doses (≥0.5 mg/kg)
are administered, hypotension, tachycardia, and skin flushing are frequent manifestations. Bronchospasm
may also occur. These responses can be avoided by slow injection of atracurium over 1 to 3 minutes or by
pretreatment with H1 and H2 receptor blockade. This histamine release, which occurs in virtually every
subject given a large enough dose, should not be confused with an anaphylactic reaction, which is
observed irrespective of dose in a small number of individuals. Anaphylactic reactions to atracurium have
been described, but they do not appear to be more frequent than after other neuromuscular blocking
drugs.27
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Special Situations
Dosage requirements are similar in the elderly, younger adults, and children, presumably reflecting the
organ independence of atracurium's elimination. Similarly, no dosage adjustment is required in individuals
with renal or hepatic failure. As with other nondepolarizing agents, the dose must be increased in burn
patients, partly because of increased protein binding and partly because of up-regulation of receptors,
causing resistance at the endplate. In the obese patient, the dose of atracurium, as for all neuromuscular
blocking agents, should be calculated based on lean body mass.
Clinical Uses
To obtain adequate intubating conditions, relatively large doses must be used (0.5 mg/kg), and
laryngoscopy should be attempted only after 2 to 3 minutes. Cardiovascular manifestations of histamine
release are often seen at that dose, and perfect intubating conditions are seen in only half the patients
(Fig. 20-3).8 Increasing the dose may improve intubating conditions, but at the expense of greater
cardiovascular effects. For intubation, there has been a tendency to replace atracurium by agents with a
shorter onset time and more cardiovascular stability, such as rocuronium. However, atracurium is
convenient and versatile for maintenance of relaxation, either as a continuous infusion (5 to 10
µg/kg/min) or as intermittent injections (0.05 to 0.1 mg/kg every 10 to 15 minutes).
Cisatracurium
In an attempt to increase the margin of safety between the neuromuscular blocking dose and the
histamine-releasing dose, a potent isomer of atracurium, cisatracurium, was identified. Like atracurium,
its cardiovascular effects are manifest only at doses exceeding 0.4 mg/kg, but its ED95 (0.05 mg/kg) is
much lower. As a result, manifestations of histamine release are not seen in practice. The metabolism of
cisatracurium is similar to that of atracurium, with Hofmann and ester hydrolysis both playing a role.52
Pharmacology
Because cisatracurium is a potent drug, its onset time is longer than that of atracurium and longer still
than that of rocuronium. For example, equipotent doses of cisatracurium (0.092 mg/kg) and rocuronium
(0.72 mg/kg) had onset times of 4 minutes and 1.7 minutes, respectively.54 The elimination half-life (22 to
25 minutes) is similar to that of atracurium,55 so the duration of action for 2 × ED95 doses (0.1 mg/kg) is 30
to 45 minutes. However, in an attempt to accelerate onset, the recommended intubating dose is
increased to 0.15 mg/kg. This dose is well below the threshold for histamine release, but the duration of
action is prolonged to 45 to 60 minutes.
Because the doses required to obtain paralysis are considerably less for cisatracurium than for
atracurium, less laudanosine and less acrylate byproducts are produced.52,53 Thus, the concerns raised by
the potential toxic effects of these metabolites are virtually eliminated.
Special Situations
Like atracurium, there is no need to adjust dosage in the elderly, children, or infants, when compared
with young adults. The experience in burn patients is limited, but the same principles that are valid for
atracurium are expected to apply. In obese individuals, the dose of cisatracurium should be calculated on
the basis of ideal body weight.56
Side Effects
In contrast to atracurium, cisatracurium is devoid of histamine-releasing properties even at high doses (8
× ED95). It is also devoid of cardiovascular effects. However, anaphylactic reactions have been described.27
Clinical Use
Cisatracurium may be used to facilitate tracheal intubation at doses equivalent to 3 to 4 times the ED95
(0.15 to 0.2 mg/kg) when manual ventilation is possible after induction of anesthesia and when the
duration of the procedure is expected to exceed 1 hour. Duration is shorter with lower doses, but onset
time is prolonged and intubating conditions are less ideal. Neuromuscular blockade is easily maintained
at a stable level by continuous intravenous infusion of cisatracurium (1 to 2 µg/kg/min) at a constant rate
and does not change with time, suggesting the lack of a significant cumulative drug effect and lack of
dependence on renal and/or hepatic clearance mechanisms.57 The rate of recovery is independent of the
dose of cisatracurium and the duration of the administration.
Because cisatracurium does not depend on end-organ function for its elimination, the drug appears
suitable for administration in the intensive care unit (ICU). The infusion rates to keep patients paralyzed
are greater than in the operating room (typically 5 µg/kg/min), with wide interindividual variability.58 It is
likely that prolonged exposure of the receptors to a neuromuscular blocking agent causes some upregulation, with a corresponding requirement for a higher dose.49
Doxacurium
Doxacurium is a potent, long-acting benzylisoquinoline compound that is not degraded by Hofmann
elimination or ester hydrolysis. It has a prolonged elimination half-life (1 to 2 hours) and depends on the
kidney and the liver for its disposition. Thus, duration of action is prolonged in the elderly and in subjects
with impaired renal or hepatic function. The ED95 for doxacurium is 25 µg/kg (Table 20-2).59 Doxacurium
has a limited place in clinical practice because of its very slow onset and long duration of action.
Nevertheless, its cardiovascular stability may be useful in patients with ischemic heart disease who are
undergoing prolonged anesthesia or long-term mechanical ventilation of the lungs. It is unsuitable for
facilitating tracheal intubation or for providing skeletal muscle relaxation during brief surgical
procedures. When infused for several days to patients in the ICU, recovery after stopping the infusion
exceeded 10 hours.
Gallamine
Gallamine was introduced in 1948 and has only historical interest. It is a low potency nondepolarizing drug
(ED95 = 2 mg/kg) with a long duration of action. Gallamine produces significant tachycardia because of a
vagolytic effect, even at doses associated with incomplete blockade at the adductor pollicis muscle. It is
effective when used to prevent succinylcholine-induced fasciculations.20
Gantacurium
Gantacurium is a new compound, still under investigation. It is a nondepolarizing drug and belongs to the
class of asymmetric mixed-onium chlorofumarates. Its main degradation pathway involves cysteine in the
plasma and is independent of plasma cholinesterase. The ED95 in humans is approximately 0.19 mg/kg.60
Cardiovascular effects are observed at doses exceeding 3 × ED95, and are most probably related to
histamine release. At doses anticipated to be required for tracheal intubation (0.4 to 0.6 mg/kg), onset at
the adductor pollicis muscle is 1.5 minutes and duration to 25% T1 recovery is 8 to 10 minutes, comparable
with that of succinylcholine.
Metocurine
Metocurine, produced by methylation of two hydroxy groups of d-tubocurarine, is twice as potent as the
parent compound
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and produces less histamine release. Its ED95 is approximately 0.3 mg/kg.47 Its duration of action is
comparable with that of d-tubocurarine, making it a long-acting agent. Metocurine enjoyed a brief period
of popularity before the introduction of atracurium and vecuronium. Metocurine and pancuronium
combined were found to be synergistic with opposing cardiovascular effects, and the mixture was
recommended for use in patients with severe cardiovascular disease. However, the introduction of
shorter-duration alternatives without cardiovascular effects has made metocurine obsolete.
Mivacurium
Mivacurium is a benzylisoquinoline derivative with a short duration of action that is hydrolyzed by plasma
cholinesterase, like succinylcholine.61 Contrary to succinylcholine, however, mivacurium produces
nondepolarizing blockade. The drug is presented as a mixture of three isomers. Two, the cis–trans and
trans–trans, have short half-lives, but the cis–cis isomer has a much longer half-life (Table 20-3). The
pharmacology of mivacurium is governed largely by the behavior of the trans–trans and cis–trans isomers,
because the cis-cis isomer accounts for only 6% of the mixture and has less potent that the other two
isomers.
Pharmacology
The ED95 of mivacurium has been estimated in the range 0.08 to 0.15 mg/kg (Table 20-2). Intubating doses
are 0.2 or 0.25 mg/kg but intubating conditions are not as good as with succinylcholine.62 Onset time is
surprisingly long for a drug whose active isomers have a terminal half-life of <2 minutes. At 2 to 3 × ED95,
twitch disappears in 2.5 to 4 minutes.61 This long onset time is probably the result of the high potency of
mivacurium.46 Recovery to 25% does not depend heavily on dose, being in the range of 15 to 25 minutes
for doses of 0.15 to 0.25 mg/kg. The infusion rate to maintain blockade constant does not vary with time,
and recovery is as rapid after many hours of infusion than after a bolus dose.61
Side Effects
Like atracurium, mivacurium releases histamine in a dose-related fashion. Hypotension, tachycardia, and
cutaneous signs, such as erythema and flushing, are seen frequently when doses are increased to 0.2
mg/kg or more. These histamine-related effects are short-lived (2 to 3 minutes) and should not normally
be considered a manifestation of anaphylaxis, which is a rare event. Bronchospasm is rare. Manifestations
of histamine release may be decreased if the drug is either given slowly (in >30 seconds) or in divided
doses (0.15 mg/kg followed 30 seconds later by 0.1 mg/kg).
Special Situations
In infants and children the ED95 is approximately the same as in adults, but onset of block and recovery
are more rapid.63 Cardiovascular effects are not as important as in adults, so doses up to 0.3 mg/kg have
been used. The infusion rate required to maintain blockade is greater in children than in adults, and less
in the elderly than in younger adults.
Burns
In burn patients, up-regulation of the receptors, and to a lesser extent increased protein binding, causes
a resistance to all nondepolarizing neuromuscular blocking agents. However, for mivacurium, the
situation is different because plasma cholinesterase activity is decreased in burn patients. The net effect
is either a normal or even an enhanced effect of usual doses.64
Reversal
Administration of anticholinesterase agents after mivacurium has been controversial. Neostigmine has
two opposing effects on mivacurium: it inhibits plasma cholinesterase, thus interfering with the
breakdown of mivacurium, but it also reverses nondepolarizing blockade. In fact, neostigmine has been
shown to delay recovery if given during intense mivacurium neuromuscular block,65 but to accelerate
recovery if signs of spontaneous recovery are present (two twitches or more present). Edrophonium does
not interfere with plasma cholinesterase activity and was found to accelerate recovery, even when given
when blockade is profound (one twitch in the train-of-four).65 Mivacurium reversal has been suggested to
be unnecessary because spontaneous recovery is rapid. However, residual block may be seen, particularly
if large doses of mivacurium are used up to the end of anesthesia.
Plasma Cholinesterase
Mivacurium is metabolized by plasma cholinesterase somewhat more slowly than succinylcholine. The
conditions associated with a decrease plasma cholinesterase activity known to affect succinylcholine
metabolism also alter mivacurium duration of action.
Clinical Use
Mivacurium is no longer available in North America, but it is used in other parts of the world. It is well
suited to surgical procedures requiring brief muscle relaxation, particularly those in which rapid recovery
is required, such as ambulatory and laparoscopic surgery. However, it is not recommended for rapidsequence induction. Cardiovascular effects may be avoided by administering the drug slowly or by
splitting the dose into two injections 30 seconds apart. Small doses of mivacurium (0.04 to 0.08 mg/kg)
have been suggested to facilitate insertion of a laryngeal mask airway. Conditions and success rate are
usually better than in the absence of neuromuscular blocking agent. Maintenance of relaxation is
accomplished more easily by constant infusion (5 to 7 µg/kg/min in young and middle-aged adults) than
by intermittent bolus injection. This infusion rate has to be increased in children and reduced in the
elderly. In children, mivacurium has a faster onset of action and more rapid recovery than in adults, so
the drug can be used for intubation and maintenance of relaxation for short procedures.63
Pancuronium
Pancuronium belongs to a series of bisquaternary aminosteroid compounds. It is metabolized to a 3-OH
compound, which has one-half the neuromuscular blocking activity of the parent compound. The ED95 of
pancuronium is 0.07 mg/kg. The duration of action is long, being 1.5 to 2 hours after a 0.15 mg/kg dose.
Clearance is decreased in renal and hepatic failure, demonstrating that excretion depends on both
organs. The onset of action is more rapid in infants and children than in adults, and recovery is slower in
the elderly.
Cardiovascular Effects
Pancuronium is associated with increases in heart rate, blood pressure, and cardiac output, particularly
after large doses (2 × ED95). The cause is uncertain but includes a vagolytic effect at the postganglionic
nerve terminal, a sympathomimetic effect as a result of blocking of muscarinic receptors that normally
exert some braking on ganglionic transmission, and an increase in catecholamine release. Pancuronium
does not release histamine.
Clinical Use
The slow onset of action of pancuronium limits its usefulness in facilitating tracheal intubation.
Administration in divided doses, with a small dose given 3 minutes before induction of anesthesia (priming
principle), produces a small but measurable acceleration. However, the intermediate-acting compounds
are more suitable when succinylcholine is contraindicated. In cardiac anesthesia, pancuronium has
enjoyed popularity because it counteracts the bradycardic effect of high doses of opioids. With the
increased tendency toward
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early extubation in cardiac surgery, the appropriateness of pancuronium in this setting must be reevaluated. The use of pancuronium instead of rocuronium is associated with a greater incidence of
muscular weakness after cardiac surgery,66 and reversal in this setting should be considered seriously. The
continued popularity of pancuronium relates to cost: generic pancuronium is cheaper than other
nondepolarizing relaxants. In noncardiac patients, its use is associated with a high incidence of residual
block in the postanesthesia care unit, even when reversal is given (Table 20-1).9,67 Pancuronium
neuromuscular block is more difficult to reverse than that of the intermediate duration agents.68
Pipecuronium
Pipecuronium was developed in an effort to obtain a pancuronium without cardiovascular side effects. Its
ED95 is slightly less (0.05 mg/kg) than that of pancuronium, and it is virtually without any cardiovascular
effects. However, pipecuronium soon became obsolete because it had the drawbacks of long-acting
agents (difficulty to reverse, residual paralysis, lack of versatility), and the absence of cardiovascular
effects was also seen with the shorter-acting vecuronium and rocuronium.
Rapacuronium
Rapacuronium is also an aminosteroid compound that was introduced for clinical use in 1999. It was
withdrawn in 2001 because of rare, but severe, cases of bronchospasm after intubation. Being less potent
than rocuronium, it had a more rapid onset of action. Following 1.5 mg/kg, good-to-excellent intubation
conditions were produced at 60 seconds, mean clinical duration was 17 minutes, and spontaneous
recovery to train-of-four ratio of 0.7 occurred in 35 minutes.69 The intubating conditions were not as good
as with succinylcholine and the duration of action was longer. Rapacuronium is metabolized to an active
17-OH derivative (ORG 9488) that has twice the neuromuscular blocking activity of the parent compound
and is excreted slowly via the kidneys.
Rapacuronium produced mild dose-related tachycardia and hypotension. Increases in airway pressure and
bronchospasm were observed in more patients given rapacuronium than succinylcholine.69 The mechanism
for this effect is not an allergic or histamine-related reaction, but is most likely related to the effect of
rapacuronium on M2 and M3 muscarinic receptors in the lung. Activation of the postsynaptic M3 receptors
by acetylcholine produces bronchosconstriction in the lungs, and the effect is terminated by presynaptic
M2 receptors that counteract this effect. Rapacuronium has the potential to block both receptors, but it
has a greater affinity for the M2 receptor. The concentrations required for M2 blockade are well within
the clinical range, while much more is required for M3 inhibition. The net effect is that if M2 receptors
are blocked selectively, for example, in susceptible individuals, bronchoconstriction by activation of the
M3 receptors is unopposed.70 Other neuromuscular blocking agents, such as vecuronium and
cisatracurium, have similar differential effects on the M2 and M3 receptors, but at concentrations higher
than encountered clinically.70
Rocuronium
Rocuronium is an aminosteroid compound with structural similarity with vecuronium and pancuronium. Its
duration of action is comparable with that of vecuronium, but its onset is shorter.
Pharmacology
Plasma concentrations of rocuronium decrease rapidly after bolus injection because of hepatic uptake.71
Thus, the duration of action of the drug is determined chiefly by redistribution, rather than by its rather
long terminal elimination half-life (1 to 2 hours; Fig. 20-10). Metabolism to 17-deacetylrocuronium is a
very minor elimination pathway. Most of the drug is excreted unchanged in the urine, bile, or feces.71
With an ED95 of 0.3 mg/kg, rocuronium has one-sixth the potency of vecuronium, a more rapid onset, but
a similar duration of action and similar pharmacokinetic behavior. With equipotent doses, rocuronium
onset at the adductor pollicis muscle is much faster than that of cisatracurium, atracurium, and
vecuronium (Fig. 20-11).46 After doses of 0.6 mg/kg (2 × ED95) maximal block occurs in 1.5 to 2 minutes. In
a multicenter study of 349 patients, intubating conditions at 60 seconds after 0.6 mg/kg rocuronium were
good to excellent in 77% of cases. To obtain results similar to those after 1 mg/kg succinylcholine, the
dose of rocuronium had to be increased to 1.0 mg/kg, which provided 92% good or excellent conditions.72
However, the duration of action is longer than for succinylcholine, ranging between 30 and 40 minutes for
a 0.6-mg/kg dose to approximately 60 minutes after 1 mg/kg in adults. Thus, rocuronium is an
intermediate-duration drug.
As for other nondepolarizing agents, the onset of action of rocuronium is more rapid at the diaphragm
and adductor laryngeal muscles than at the adductor pollicis muscle,73 probably a result of a greater blood
flow to centrally located muscles. Laryngeal adductor muscles are important in anesthesia because they
close the vocal cords and insufficient relaxation prevents easy passage of the tracheal tube. Laryngeal
adductor muscles are resistant to the effect of rocuronium, and the plasma concentration required for
equivalent blockade is greater at the larynx than at the adductor pollicis muscle.74 The same is true of the
diaphragm, which is resistant to the effect of rocuronium and other neuromuscular blocking agents.
Recovery is faster at the diaphragm and larynx than at the adductor pollicis muscle.75
Cardiovascular Effects
No hemodynamic changes (blood pressure, heart rate, or ECG) were seen in humans, and there were no
increases in plasma histamine concentrations after doses of up to 4 × ED95 (1.2 mg/kg).76 Only slight
hemodynamic changes are observed during coronary artery bypass surgery. Anaphylactic reactions have
been described, and a French study indicated that these events occurred more frequently with
rocuronium than with other neuromuscular blocking agents,27 contrary to the findings of an Australian
study.77 However, it now appears that many of these reports might not be a true anaphylactic reaction to
rocuronium because up to 50% of the general population show a positive intradermal or pick test to the
drug.78 Clearly, many patients who were investigated for a possible anaphylactic reaction were falsely
labeled allergic to the drug because of the high rate of false-positive tests. It is possible that
overdiagnosis has played a role in the relatively high incidence of rocuronium anaphylaxis reported in
Norway (29 cases in 150,000 administrations, or 1:5,000)79 or in France,27 while reports from other Nordic
countries suggest a much lower incidence (7 cases in 800,000 administrations, or <1:100,000).79
Another hypothesis that was put forward recently is sensitization of patients by over-the-counter cough
medication containing pholcodine. In a study comparing subjects from Norway, where the number of
reported anaphylactic cases is high, and Sweden, where those reports are virtually nonexistent, it was
found that a large proportion of Norwegians was sensitized to pholcodine, but this sensitization did not
occur in Swedes.80 Pholcodine is available as an antitussive in cough syrups in certain countries like
Norway, France, Ireland, the United Kingdom, and Australia. It is not available in Sweden, Denmark,
Germany, the United States, and Canada. In the United States, the incidence of anaphylactic reactions to
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rocuronium and vecuronium may be as low as 1:1,000,000.81 It is hypothesized that cross-sensitization may
occur between pholcodine and neuromuscular blocking agents such as rocuronium and succinylcholine.
However, its should be remembered that the role of pholcodine in the context remains a hypothesis, and
the incidence of anaphylactic reactions to rocuronium remains very low, even in countries where
pholcodine is available. Thus, current evidence suggests that withholding rocuronium because of the fear
of anaphylactic reactions is unjustified.
Special Situations
The potency of rocuronium has been reported to be slightly greater in women than in men, the ED95 being
0.27 and 0.39 mg/kg, respectively, with an increased duration in women.82 Some ethnic groups are more
sensitive to the drug. Chinese subjects living in Vancouver were found to be more sensitive than whites.83
As with other nondepolarizing drugs, potency has been reported to vary according to geographical
distribution. Most studies reported a greater potency in North America compared with Europe,84 with one
report showing a potency of rocuronium in mainland China as intermediate between European and
American values.84 Children (2 to 12 years old) require more rocuronium and duration of action is less.
Onset of action is shorter in the pediatric than in the adult population. For example, a dose of 1.2 mg/kg
provides an onset time (39 seconds) comparable with that of succinylcholine, 2 mg/kg, and mean duration
of action is 41 minutes.85 Thus, the recommended doses are 0.9 to 1.2 mg/kg in this age group.
Rocuronium is more potent in infants than in older children. Doses of 0.6 mg/kg have a longer duration in
neonates (<1 month) than in infants (5 to 12 months), so a reduced dosage (0.45 mg/kg) is
recommended.86 Rocuronium may be used for rapid-sequence induction as succinylcholine is relatively
contraindicated because of the possible presence of undiagnosed muscle dystrophy in pediatric patients,
especially in boys.34 The use of rocuronium in large doses (1.2 mg/kg) might become widespread in all age
groups for rapid-sequence induction if and when the selective binding agent sugammadex becomes
available (see “Sugammadex”).
In elderly patients, the ED95 is similar to that found in younger adults, but the duration of action is
prolonged slightly.87 Rocuronium has an increased terminal half-life in renal-failure patients, probably
because of its partial renal elimination, but this translates into very minor, if any, prolongation of block.88
In hepatic disease, the slower uptake and elimination of rocuronium by the liver tends to prolong the
duration of action of the drug, but this is compensated to some extent by the larger volume of
distribution.89
Clinical Use
The rapid onset and intermediate duration of action makes this agent a potential replacement for
succinylcholine in conditions where rapid tracheal intubation is indicated. However, large doses (>1
mg/kg) are required, with the drawback being a prolonged duration of action. Contrary to
succinylcholine, the option to wait for spontaneous breathing to resume before hypoxia is manifest does
not exist with rocuronium. To shorten the onset time, the “priming principle,” which involves the
administration of a small dose of rocuronium usually 3 minutes before induction, has been advocated.
Unfortunately, the optimal priming dose, that is the largest dose that will not produce symptoms of
weakness in the awake patient, is rather small. As with defasciculating doses before succinylcholine, it is
not recommended to administer more than 0.1 × ED95,28 which, in the case of rocuronium, amounts to 0.03
mg/kg. Such a small dose has minimal effects on onset times provided by much larger doses (0.6 to 1.0
mg/kg). However, priming might have an effect if the intubating dose is small (0.45 mg/kg). A “timing
principle” has been described in which 0.6 mg/kg rocuronium is given before the induction agent, which
is administered at the onset of ptosis. Considering that loss of consciousness does not occur immediately
after injection of the induction agent, this technique is not recommended. Rocuronium and thiopental do
not mix. They form a precipitate when they are in the same intravenous line. If thiopental is used for
induction of anesthesia, the line must be flushed carefully before rocuronium is given.
Rocuronium has gradually replaced vecuronium as an intermediate-duration relaxant because of its more
rapid onset. Initial doses of 0.6 mg/kg intravenously will usually produce good intubating conditions
within 90 seconds. Duration of action is 30 to 40 minutes. Smaller doses (typically, 0.45 mg/kg) have a
shorter duration of action, but time to intubation must be increased. Subsequent doses of 0.1 to 0.2
mg/kg will provide clinical relaxation for 10 to 20 minutes. Alternatively, rocuronium might be given by
continued infusion, titrated with the help of a nerve stimulator. Infusion rates are in the range 5 to 10
µg/kg/min.57 Recovery after infusions is slower than after bolus doses.
Vecuronium
Vecuronium is an intermediate-duration aminosteroid neuromuscular relaxant without cardiovascular
effects. Its ED95 is 0.04 to 0.05 mg/kg. Its duration and recovery characteristics are comparable with those
of rocuronium. However, its onset of action is slower.
Pharmacology
Vecuronium is a monoquaternary ammonium compound produced by demethylation of the pancuronium
molecule. Vecuronium undergoes spontaneous deacetylation to produce 3-OH, 17-OH, and 3,17-(OH)2
metabolites. The most potent of these metabolites, 3-OH vecuronium, about 60% of the activity of
vecuronium, is excreted by the kidney and may be responsible, in part, for prolonged paralysis in patients
in the ICU. Like rocuronium, vecuronium has been found less potent and with a shorter duration of action
in men than in women, probably because of a greater volume of distribution in men.
Duration of action of vecuronium, like that of rocuronium, is governed by redistribution, not by
elimination (Fig. 20-10). Attempts have been made to speed the onset of action by using the priming
principle, that is, by administering a small, subparalyzing dose several minutes before the principal dose
is given. With the availability of rocuronium, which has a more rapid onset of action than that of
vecuronium, “priming” becomes an obsolete practice.
Cardiovascular Effects
Vecuronium usually produces no cardiovascular effects with clinical doses. It does not induce histamine
release. Bradycardia has been described with high-dose opioid anesthesia, and this might be the
reflection of the opioid effect. Allergic reactions have been described, but no more frequently than after
the use of other neuromuscular blocking drugs.27,81
Clinical Use
The cardiovascular neutrality and intermediate duration of action make vecuronium a suitable agent for
use in patients with ischemic heart disease or those undergoing short, ambulatory surgery. As with
rocuronium, care should be taken when vecuronium is administered immediately after thiopental because
a precipitate of barbituric acid may be formed that may obstruct the intravenous cannula.
Large doses (0.1 to 0.2 mg/kg) can be used to facilitate tracheal intubation instead of succinylcholine.
For maintenance of relaxation, vecuronium may be given using intermittent boluses, 0.01 to 0.02 mg/kg,
or by continuous infusion at a rate of 1 to 2 µg/kg/min. However, the rate of spontaneous recovery of
neuromuscular function is slowerafter administration
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by infusion than by intermittent boluses.90 Vecuronium has now largely been replaced by the more rapid
rocuronium.
Drug Interactions
Interactions between neuromuscular blocking drugs and several anesthetic and nonanesthetic drugs have
been suggested. Although some interactions have been confirmed, many remain as isolated case reports
or theoretical possibilities. Only some of the most clinically relevant interactions will be discussed here.
Anesthetic Agents
Inhalational Agents
The anesthetic vapors potentiate neuromuscular blockade in a dose-related fashion. Studies attempting
to quantify the magnitude of this effect have led to conflicting results because the time factor is also
important. The older halogenated agents halothane, enflurane, and isoflurane may take 2 hours or more
to equilibrate with muscle, so in practice the potentiating effect of these vapors might not be
immediately apparent. At similar minimum alveolar concentration (MAC), enflurane appears to potentiate
nondepolarizing blockade more than does isoflurane, which in turn potentiates to a greater extent than
halothane. The newer agents sevoflurane and desflurane equilibrate more rapidly with muscle, but the
effect may be measurable only after 30 minutes or more. For example, the duration of action of a bolus
dose of mivacurium given at induction of anesthesia is not altered by the presence of sevoflurane (1
MAC). However, the infusion rate required to maintain block decreases by 75% over the next 1.5 hours,
compared with no change under propofol anesthesia.91 The degree of potentiation increases with the
concentration of sevoflurane. Recovery rate is longer in the presence of sevoflurane, even if the infusion
rate of mivacurium was less. There is evidence that desflurane might have a greater potentiating effect
on the neuromuscular junction than sevoflurane.92
Nitrous oxide (70% inspired) has been considered as having no effect on neuromuscular blockade. Recent
evidence suggests that the presence of nitrous oxide has a slight potentiating effect on neuromuscular
block, decreasing the ED50 of rocuronium by approximately 20%.93
The mechanism of action of potentiation by halogenated agents is uncertain, but it appears that they
produce their effects at the neuromuscular junction. Isoflurane and sevoflurane inhibit current through
the nicotinic receptor at the neuromuscular junction, and this inhibition is dose-dependent.94
Intravenous Anesthetics
Although some slight potentiation of neuromuscular blockade has been demonstrated with high doses of
most intravenous induction agents in animals, clinical doses of drugs such as midazolam, thiopental,
propofol, fentanyl, and ketamine have little or no neuromuscular effect in humans.
Local Anesthetics
Lidocaine, procaine, and other local anesthetic agents produce neuromuscular blockade in their own
right as well as potentiating the effects of depolarizing and nondepolarizing neuromuscular blocking
drugs. Contrary to the findings of other studies, a longer duration of action of vecuronium was found in
patients under general anesthesia with an epidural catheter injected with mepivacaine.95 The exact
mechanisms for this interaction are uncertain, but it is unlikely that the systemic levels of local
anesthetic are sufficient to produce this effect at the neuromuscular junction.
Interactions Between Nondepolarizing Blocking Drugs
Combinations of two nondepolarizing neuromuscular blocking drugs are either additive or synergistic,
depending on which two drugs are involved. Addition occurs when the total effect equals that of
equipotent doses of each drug. For instance, pancuronium and vecuronium have an additive interaction.96
An ED95 of either pancuronium (0.07 mg/kg) or vecuronium (0.05 mg/kg) yields 95% blockade. Half the ED95
of pancuronium (0.035 mg/kg) administered with half the ED95 of vecuronium (0.025 mg/kg) will also
produce 95% block. However, some combinations are synergistic; that is, their combined effect is greater
than if an equipotent dose of either one of the constituents is given alone. For example, cisatracurium
(ED95 = 0.05 mg/kg) and rocuronium (ED95 = 0.3 mg/kg) will produce a greater blockade than equipotent
amounts of each drug given alone. If half the ED95 of cisatracurium (0.025 mg/kg) is administered with half
the ED95 of rocuronium (0.15 mg/kg), the effect will be >95% twitch depression. To get 95% block, only
approximately one-fourth the ED95 of each drug needs to be given together; that is, cisatracurium, 0.0125
mg/kg with rocuronium, 0.075 mg/kg.97 Generally, combinations of chemically similar drugs—for example,
pancuronium– vecuronium, d-tubocurarine–metocurine, and atracurium– mivacurium—have additive
effects. Combinations of dissimilar agents tend to show potentiation, but the rule is not always followed.
The first such synergism was demonstrated for pancuronium–metocurine combinations, and the mixture
was advocated for its lack of cardiovascular effects. The use of combinations may be recommended to
reduce cost or to take advantage of the properties of two drugs. For example, synergism occurs between
mivacurium and rocuronium, and the mixture retains the fast onset of rocuronium, while having the short
duration of action of mivacurium.
The mechanism by which two drugs produce a greater effect than either one alone is uncertain.
Synergism is expected between mivacurium and pancuronium because of the inhibition of plasma
cholinesterase that pancuronium produces, thus accentuating the effect of mivacurium. However, such a
simple mechanism is absent in most cases. Surprisingly, when drug mixtures are applied to receptors in
vitro, no potentiation is observed.98
Interactions of a different nature occur when administration of a nondepolarizing agent is followed by
injection of another nondepolarizing agent. Usually, the duration of action of the second agent is that of
the first drug given. For example, if vecuronium, an intermediate-acting agent, is given after the longacting pancuronium, it has a long duration of action.99 On the contrary, if vecuronium is the first drug,
pancuronium given as a top-up dose has an intermediate duration of action. Thus, switching from a longduration agent to an intermediate-duration drug to obtain paralysis of intermediate duration at the end of
a case will not provide paralysis of intermediate duration. The reason why the characteristics of the first
agent given are determinant is that the size of the loading dose is greater than that of the maintenance
dose, so that even when the second dose is given, the majority of receptors is still occupied by the first
drug.
Nondepolarizing–Depolarizing Interactions
Depolarizing and nondepolarizing relaxants are mutually antagonistic. When d-tubocurarine or other
nondepolarizing agents are given before succinylcholine to prevent fasciculations and muscle pain, the
succinylcholine is less potent and has a shorter duration of action.22 The exception is with pancuronium
because it inhibits plasma cholinesterase. However, nondepolarizing drugs are somewhat more effective
when administered after the effect of succinylcholine has worn off, compared with no prior
succinylcholine.17 Finally, the response to a small dose of succinylcholine at the end of an anesthetic in
which a nondepolarizing agent has been used is
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difficult to predict. It may either antagonize or potentiate the blockade, depending on the degree of
nondepolarizing block. Antagonism is more likely if blockade is deep and potentiation if blockade is
shallow. If an anticholinesterase agent has been given, then the effect of the succinylcholine is
potentiated because of inhibition of plasma cholinesterase.
Antibiotics
Neomycin and streptomycin are the most potent of the aminoglycosides in depressing neuromuscular
function.100 The polymyxins also depress neuromuscular transmission.100 These antibiotics are no longer
used frequently. Other aminoglycosides (e.g., gentamicin, netilmicin, tobramycin) also potentiate
nondepolarizing neuromuscular blockade. They prolong the action of steroidal neuromuscular agents,
but their effect on benzylisoquinoline compounds is less apparent.101 The lincosamides clindamycin and
lincomycin have prejunctional and postjunctional effects, but prolongation of blockade by clindamycin is
unlikely to occur clinically unless large doses are used. The penicillins, cephalosporins, tetracyclines, and
erythromycin are devoid of neuromuscular effects at clinically relevant doses. Metronidazole does not
appear to have clinically significant effects at the neuromuscular junction.
Anticonvulsants
Acute administration of phenytoin produces augmentation of neuromuscular block.102 Resistance to
pancuronium, metocurine, vecuronium, and rocuronium has been demonstrated in patients receiving
chronic anticonvulsant therapy with carbamazepine or phenytoin.103,104 The requirements for atracurium,
mivacurium, and cisatracurium are the same or increased slightly by chronic administration of
anticonvulsant drugs.105 A least part of the phenomenon has a pharmacokinetic origin. In patients with
chronic carbamazepine therapy, the clearance of vecuronium was found to be increased and its terminal
half-life decreased.103
Cardiovascular Drugs
Beta-blocking drugs and calcium channel antagonists have been found to have neuromuscular effects in
vitro, but in practice, the duration of action of neuromuscular blocking agents is not altered in patients
taking these drugs chronically.104 Ephedrine given at induction of anesthesia has been found to accelerate
onset of action of rocuronium while esmolol prolongs onset time.106 The mechanism for this effect is
probably by alteration of drug delivery to the site of action by changes in cardiac output. It is possible to
take advantage of this phenomenon to improve intubating conditions. Use of ephedrine, 5 to 10 mg in the
average adult, at induction has been shown to improve intubating conditions provided by rocuronium.107
Magnesium
Calcium is required for the release of acetylcholine,12 and magnesium antagonizes this effect. In doses of
30 mg/kg at induction followed by 10 mg/kg/hr, magnesium was found to reduce maintenance
rocuronium requirements by 50% and to increase recovery times.108 Similar effects have been reported
with other nondepolarizing agents. Previous administration of magnesium abolishes succinylcholineinduced fasciculations, but it does not prolong the duration of neuromuscular blockade.109
Miscellaneous
Metoclopramide inhibits plasma cholinesterase and thus prolongs the action of succinylcholine and
mivacurium. Inconsistent interactions have been described for diuretics, digoxin, and corticosteroids,
probably because these drugs induce chronic fluid and electrolyte shifts, the magnitude of which depends
on the condition being treated.
Altered Responses to Neuromuscular Blocking Agents
Intensive Care Unit
Neuromuscular blocking agents are useful in the ICU to facilitate mechanical ventilation, and their use is
frequent in patients requiring ventilation in the prone position, permissive hypercapnia, high positive endexpiratory pressure, and elevated airways pressure.110 It is essential to provide sedation to patients who
receive paralyzing agents, to prevent discomfort associated with the inability to move. Enthusiasm for
the liberal use of neuromuscular blocking agents in the ICU has waned considerably over the past 10 to
20 years because of several reports of critically ill patients who demonstrated residual weakness for
unexpectedly long periods after discontinuation of a neuromuscular blocking agent. In some, recovery
took several months.111 Pancuronium and vecuronium have been used most frequently, but recent
descriptions of similar syndromes after atracurium and cisatracurium suggest that the frequency of
reports of weakness reflects the popularity of the drugs rather than a particular association with steroidbased compounds. Electromyographic studies have shown variable lesions from myopathy to axonal
degeneration of motor and sensory fibers. The picture is complicated by the syndrome of “critical illness
neuropathy,” which occurs in patients with sepsis and multiorgan failure, even in individuals not given
neuromuscular blocking agents. Administration of corticosteroids is also considered a risk factor.110
Symptoms include failure to wean from mechanical ventilation, limb weakness, and impaired deep tendon
reflexes, but sensory function is usually not affected. There are no controlled clinical studies to allow the
several initiating factors to be identified and matched with particular syndromes. In the absence of more
definitive studies, it is recommended to administer neuromuscular blocking agents only to patients who
cannot be managed otherwise, to limit the duration of administration to a few days or less, to use only
the dose that is necessary, and to interrupt temporarily the administration of the neuromuscular
blocking agent every day or so.110
Studies in ICU patients in whom the administration of relaxant was adjusted according to strict
neuromuscular monitoring criteria have shown considerable variation in the requirement for
neuromuscular blocking agent to maintain the same effect among patients and a wide within-patient
pharmacokinetic variability.58 Vecuronium and rocuronium have been associated with prolonged recovery
times. For example, a mean of 3 hours was found between the end of rocuronium infusion and a train-offour ratio of 0.7.112 With cisatracurium, this interval was shorter (approximately 1 hour) and less
variable.58 Drug requirement is variable from patient to patient, is usually greater than in the operating
room, and tends to increase with time. These reports suggest the need for more careful monitoring of
neuromuscular block in ICU patients, although the optimal method and level of block to be achieved are
uncertain. It is suggested to titrate neuromuscular blocking agents to the minimum infusion rate that
will optimize oxygenation.
Myasthenia Gravis
Myasthenia gravis is an autoimmune disease in which circulating antibodies produce a functional reduction
in the number of postsynaptic acetylcholine receptors.113
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Diagnosis and Management
The hallmark of myasthenia gravis is fatigue. Presentation is extremely varied but typically, ocular
symptoms, such as diplopia and ptosis, occur first. Bulbar involvement is usually seen next. Patients may
proceed to have extremity weakness and respiratory difficulties.113 The characteristic EMG finding in
myasthenia gravis is a voltage decrement to repeated stimulation at 2 to 5 Hz. This finding is also
characteristic of nondepolarizing blockade in nonmyasthenic individuals. Edrophonium, 2 to 8 mg,
produces brief recovery from myasthenia gravis and can be used as a diagnostic test. Finally, up to 80% of
patients have an increased titer of the acetylcholine receptor antibody.
Treatment is largely symptomatic. Anticholinesterase agents such as pyridostigmine are used to increase
neurotransmission at the neuromuscular junction. Corticosteroids and immunotherapy with azathioprine
might produce long-term improvement. Plasmapheresis might be effective by eliminating the circulating
antibody. Finally, many myasthenic patients have an associated thymoma, and surgical removal of the
thymus may be indicated.113
Response to Neuromuscular Blocking Agents
Patients with myasthenia gravis are usually resistant to succinylcholine, with larger than usual doses
required to produce complete blockade. This effect might be offset by the inhibition of plasma
cholinesterase activity provided by pyridostigmine. Sensitivity to nondepolarizing neuromuscular
blocking drugs is increased to a variable extent, depending on the severity of the disease. The ED95 of
vecuronium was found to be decreased by more than half in myasthenic patients, and the response of the
orbicularis oculi muscle is depressed even more than that of the adductor pollicis muscle, reflecting some
degree of ocular involvement.114
Management of Anesthesia
Traditionally, neuromuscular blocking drugs have been avoided in the patient with myasthenia gravis by
the use of inhalational vapors with or without local anesthesia. More recently, there have been several
reports of the successful use of small, titrated doses of atracurium, mivacurium, vecuronium, or
rocuronium, administered under careful neuromuscular monitoring.113 The effect of reversal drugs might
be less than expected because myasthenic patients already receive drugs that produce cholinesterase
inhibition. Thus, it is preferable to continue mechanical ventilation until spontaneous recovery is
manifest.
After thymectomy, the need for mechanical support of ventilation can usually be predicted from
preoperative lung function tests. The dose of anticholinesterases should be adjusted and is usually is
reduced for 1 to 2 days after surgery.
Myotonia
Myotonia is characterized by an abnormal delay in muscle relaxation after contraction. Several forms have
been described: myotonic dystrophy (dystrophia myotonica, myotonia atrophica, Steinert disease),
myotonia congenita (Thomsen disease), hyperkalemic periodic paralysis, and paramyotonia congenita.
Diagnosis
Repeated nerve stimulation leads to a gradual but persistent increase in muscle tension. The EMG is
pathognomonic; myotonic after-discharges are seen in peripheral muscle, consisting of rapid bursts of
potential produced by tapping the muscle or moving the needle. They produce typical “dive-bomber”
sounds on the loudspeaker.
Response to Neuromuscular Blocking Agents
The characteristic response to succinylcholine is a sustained, dose-related contracture that may make
ventilation difficult for several minutes. Muscle membrane fragility may be responsible for the
exaggerated hyperkalemia that is produced after succinylcholine.34 Most case reports suggest that the
response to nondepolarizing drugs is normal. However, myotonic responses have been observed after
reversal with neostigmine.
Anesthesia
Succinylcholine is best avoided. Short- or intermediate-duration nondepolarizing agents may be used in
usual doses with careful neuromuscular monitoring. Reversal agents are best avoided. Thus, mechanical
ventilation should be maintained until the effects of nondepolarizing agents have worn off completely.
Muscular Dystrophy
The muscular dystrophies are a group of many diseases, with variability in presentation and typical age at
onset of symptoms. The most common of these is the Duchenne-type muscular dystrophy (DMD), an Xlinked hereditary disease that usually becomes apparent in childhood. Other types of muscular dystrophy
include Becker, limb-girdle, fasciohumeral, Emery-Dreifuss, nemaline rod, and oculopharyngeal
dystrophy. There have been several reports of cardiac arrest after administration of succinylcholine in
children, often associated with hyperkalemia. Resuscitation was found to be difficult, and several of
these cases were fatal.34 The most likely explanation for these adverse events is previously undiagnosed,
latent, muscular dystrophy.
Response to Neuromuscular Blocking Agents
In most case reports, the response to nondepolarizing agents, such as vecuronium, atracurium, and
mivacurium, has been described as normal, although there have been sporadic instances of increased
sensitivity. There are little data on the response to anticholinesterases. There is considerable controversy
over whether DMD patients are susceptible to malignant hyperthermia.
Anesthesia
Succinylcholine should be avoided in patients with muscular dystrophy, especially if onset of symptoms
occurred in childhood or adolescence. The possibility of latent or unrecognized DMD in young males (<10
years old) may be a reason to avoid succinylcholine in this patient population. Careful titration of shortor intermediate-duration nondepolarizing agents should be done. Reversal agents do not appear to be
contraindicated.
Upper Motor Neuron Lesions
Patients with hemiplegia or quadriplegia as a result of central nervous system lesions show an abnormal
response to both depolarizing and nondepolarizing agents. Hyperkalemia and cardiac arrest have been
described after succinylcholine, probably as a result of extrajunctional receptor proliferation.
Hyperkalemia is typically seen if the drug is given between from 1 week to 6 months after the lesion, but
may be seen before and after that period.34 There is resistance to nondepolarizing neuromuscular
blocking drugs below the level of the lesion. In hemiplegic patients, monitoring of the affected side
shows that the block is less intense and recovery is more rapid than on the unaffected side. However, the
apparently normal
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side also demonstrates some resistance to nondepolarizing drugs. Similar findings have been reported
after a stroke, with a greater resistance on the affected side.
Burns
As a result of the proliferation of extrajunctional receptors, succinylcholine produces severe hyperkalemia
in patients with burns, and this may lead to cardiac arrest. The magnitude of the problem depends on the
extent of the injury. It may appear as early as 24 to 48 hours after the burn injury and usually ends with
healing.34 Resistance to the effects of nondepolarizing neuromuscular blocking agents is manifest, even
in muscles that are apparently not affected by the burn.49,50
Miscellaneous
Denervated muscle demonstrates potassium release after succinylcholine and resistance to
nondepolarizing relaxants. Contractures in response to succinylcholine have also been observed in
amyotrophic lateral sclerosis and multiple sclerosis. There have been isolated reports of hyperkalemia
after succinylcholine in several neurologic diseases, including Friedrich's ataxia, polyneuritis, and
Parkinson disease.
Monitoring Neuromuscular Blockade
Why Monitor?
Deep levels of paralysis are usually desired during anesthesia to facilitate tracheal intubation and to
obtain an immobile surgical field. However, complete return of respiratory function must be attained
before the trachea is extubated. Administration of neuromuscular blocking drug must be individualized
because blockade occurs over a narrow range of receptor occupancy, and because there is considerable
interindividual variability in response. Thus, it is important for the clinician to assess the effect of
neuromuscular blocking drugs without the confounding influence of volatile agents, intravenous
anesthetics, and opioids. One should remember, however, that monitoring is a tool, not a cure.
Neuromuscular blocking agents have the same effects, whether or not monitoring is used. Most studies
found that monitoring is not associated with a decrease in the incidence of residual paralysis.9 To test the
function of the neuromuscular junction, a peripheral nerve is stimulated electrically, and the response of
the muscle is assessed.
Figure 20-12. Electrode placement to obtain contraction of
the adductor pollicis muscle. The traditional method is to
apply the electrodes over the course of the ulnar nerve at the
wrist, with the negative electrode distal (right). An alternate
method is to position the electrodes over the adductor pollicis
muscle (left), the negative electrode on the palm of the hand,
View Figure
the positive in the same location, but on the dorsum of the
hand. The device fixed to the thumb is an accelerometer.
Stimulator Characteristics
The response of the nerve to electrical stimulation depends on three factors: the current applied, the
duration of the current, and the position of the electrodes. Stimulators should deliver a maximum current
in the range of 60 to 80 mA. Most stimulators are designed to provide constant current, irrespective of
impedance changes because of drying of the electrode gel, cooling, decreased sweat gland function, and
so forth. However, this constant current feature does not hold for high impedances (>5 kΩ). Thus,
electrodes should be firmly applied to the skin. A current display monitor on the stimulator is an asset
because accidental disconnection can be identified easily by a current approaching 0 mA. The duration of
the current pulse should be long enough for all axons in the nerve to depolarize but short enough to avoid
the possibility of exceeding the refractory period of the nerve. In practice, pulse durations of 0.1 to 0.2
msec are acceptable. At least one electrode should be on the skin overlying the nerve to be stimulated. If
the negative electrode is used for this purpose, the threshold to supramaximal stimulation is less than for
the positive electrode. However, the difference is not large in practice. The position of the other
electrode is not critical, but it should not be placed in the vicinity of other nerves. There is no need to
use needle electrodes. Silver–silver chloride surface electrodes, used to monitor the electrocardiogram,
are adequate for peripheral nerve stimulation, without the risk of bleeding, infection, and burns. In
practice, applying these electrodes along the course of a nerve gives the best results (Fig. 20-12).
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Monitoring Modalities
Different stimulation modalities were introduced into clinical practice to take advantage of the
characteristic features of nondepolarizing neuromuscular blockade: fade and posttetanic facilitation with
high-frequency stimulation. Thus, the following discussion refers mostly to nondepolarizing block.
Single Twitch
The simplest way to stimulate a nerve is to apply a single stimulus, at intervals of >10 seconds (frequency,
<0.1 Hz). This interval is needed to allow the neuromuscular junction to recover if nondepolarizing
agents are used. With shorter intervals, fade might be present. With depolarizing agents like
succinylcholine, little fade occurs and a higher frequency, such as 1 Hz, may be used without concern for
fade. The amplitude of response is compared with a control, preblockade twitch height. The single-twitch
modality is useful to construct dose-response curves and to evaluate onset time. However, because a
control value is required, the clinical usefulness of this mode of stimulation is limited.
Tetanus
When stimulation is applied at a frequency of ≥30 Hz, the mechanical response of the muscle is fusion of
individual twitch responses. In the absence of neuromuscular blocking drugs, no fade is present and the
response is sustained. During nondepolarizing blockade, the mechanical response appears as a peak,
followed by a fade (Fig. 20-9). The sensitivity of tetanic stimulation in the detection of residual
neuromuscular blockade is greater than that of single twitch; that is, tetanic fade might be present while
twitch height is normal. Most nerve stimulators provide a 5-second train at a frequency of 50 Hz. This
frequency was adopted because at >100 Hz, some fade may be seen even in the absence of
neuromuscular blocking drugs. However, more fade is seen with 100-Hz than 50-Hz frequencies, and 100Hz, 5-second trains are most useful in the detection of residual block.44,115 With tetanic stimulation, no
control prerelaxant response is required, as the degree of muscle paralysis can be assessed by the degree
of fade following tetanic stimulation. However, the main disadvantage of this mode of stimulation is
posttetanic facilitation (Fig. 20-9), the extent of which depends on the frequency and duration of the
tetanic stimulation. For a 50-Hz tetanus applied for 5 seconds, the duration of this interval appears to be
at least 1 to 2 minutes.45 If single-twitch stimulation is performed during that time, the response is
spuriously exaggerated.
Train-of-Four
With 2-Hz stimulation, the mechanical or electrical response decreases little after the fourth stimulus,
and the degree of fade is similar to that found at 50 Hz.43 Thus, applying train-of-four stimulation at 2 Hz
provides more sensitivity than single twitch and approximately the same sensitivity as tetanic stimulation
at 50 Hz. In addition, this relatively low frequency allows the response to be evaluated manually or
visually. Moreover, the presence of a small number of impulses (four) eliminates the problem of
posttetanic facilitation. Train-of-four stimulation can be repeated every 12 to 15 seconds. There is a
fairly close relationship between single-twitch depression and train-of-four response,116 and no control is
required for the latter. During recovery, the second twitch reappears at 80 to 90% single-twitch block, the
third at 70 to 80%, and when blockade is 65 to 75%, all four twitches become visible.117 Then, the train-offour ratio, the height of the fourth twitch to that of the first twitch, is linearly related to first twitch
height when blockade is <70%. When single-twitch height has recovered to 100%, the train-of-four ratio is
approximately 70%.
Figure 20-13. Posttetanic count (PTC). During profound
blockade, no response is seen to train-of-four (TOF) or tetanus.
However, because there is posttetanic facilitation, some
twitches can be seen after tetanic stimulation. In this example,
View Figure
the PTC is 9.
Posttetanic Count
During profound neuromuscular blockade, there is no response to single-twitch, tetanic, or train-of-four
stimulation. To estimate the time required before the return of a response, one may use a technique that
depends on the principle of posttetanic facilitation. A 50-Hz tetanus is applied for 5 seconds, followed by
a 3-second pause and by stimulation at 1 Hz. The train-of-four and tetanic responses are undetectable,
but facilitation produces a certain number of visible posttetanic twitches (Fig. 20-13). The number of
visible twitches correlates inversely with the time required for a return of single-twitch or train-of-four
responses.118 For intermediate-duration drugs, the time from a posttetanic count (PTC) of 1 to
reappearance of twitch is 15 to 20 minutes.
Double-Burst Stimulation
Train-of-four fade may be difficult to evaluate by visual or tactile means during recovery from
neuromuscular blockade. Irrespective of experience, it is difficult for anesthesiologists to detect trainof-four fade when actual train-of-four ratio is 0.4 or greater, meaning that residual paralysis can go
undetected.115 This shortcoming can be overcome, to a certain extent, by applying two short tetanic
stimulations (three impulses at 50 Hz, separated by 750 msec), and by evaluating the ratio of the second
to the first response. The double-burst stimulation ratio correlates closely with the train-of-four ratio,
but is easier to detect manually.115 At least 12 to 15 seconds must elapse between two consecutive
double-burst stimulations.
Recording the Response
Visual and Tactile Evaluation
When electrical stimulation is applied to a nerve, the easiest and least expensive way to assess the
response is to observe or feel the response of the muscle. This method is easily adaptable to any
superficial muscle. However, serious errors in assessment can be made. In the case of evaluating the
response of the adductor pollicis muscle to ulnar nerve stimulation, the train-of-four count can be made
reliably during a surgical procedure,117 but the quantitative assessment of train-of-four ratio is difficult to
make during recovery. Several investigations suggest that train-of-four ratios as low as 0.3115 can remain
undetected.
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The detection rate for tetanic fade (50 Hz) is no better.115 With double-burst stimulation, fade can be
detected reliably up to train-of-four ratios in the range of 0.6 to 0.7.115 With 100-Hz tetanic stimulation,
fade might be detected at train-of-four ratios of 0.8 to 1.044,115 and may be seen in individuals with no
neuromuscular block.
Measurement of Force
A force transducer can overcome the shortcomings of one's senses. If applied correctly, the device
provides accurate and reliable responses, displayed as either a digital or an analog signal on a monitor.
Force measurement can be measured after single-twitch, tetanus, train-of-four, double-burst, or
posttetanic stimulation. However, the availability of tetanus and double-burst stimulation is superfluous if
accurate measurement of the train-of-four response can be made. Unfortunately, transducers are
expensive, bulky, cumbersome, and can be applied to only one muscle, usually the adductor pollicis.
Electromyography
It is possible to measure the electrical instead of the mechanical response of the muscle. One electrode
should be positioned over the neuromuscular junction, which is usually close to the midportion of the
muscle, and the other near the insertion of the muscle. A third, neutral electrode can be located
anywhere else. Theoretically, any superficial muscle can be used for EMG recordings. In practice, such
recordings are limited to the hypothenar eminence, the first dorsal interosseous, and the adductor pollicis
muscles, which are supplied by the ulnar nerve. Most EMG recording devices compute the area under the
EMG curve during a specified time window after the stimulus is applied. There is usually good correlation
between EMG and force of the adductor pollicis muscle if the EMG signal is taken from the thenar
eminence. The signal obtained from the hypothenar eminence is larger and less subject to movement
artifacts, but it can underestimate the degree of paralysis when compared with the adductor pollicis
muscle.119
Accelerometry
According to Newton's law, acceleration is proportional to force if mass remains unchanged. The device is
usually attached to the tip of the thumb (Fig. 20-12) and a digital readout is obtained. The setup is
sensitive to inadvertent displacement of the thumb and, in the absence of neuromuscular blocking
drugs, train-of-four ratios >100% can be obtained.116 In spite of these shortcomings, accelerometers have
become increasingly popular because they are easy to use, are less cumbersome, can be used on muscles
other than the adductor pollicis, and are relatively inexpensive. The use of accelerometry is helpful in the
diagnosis of residual paralysis120 and, in certain circumstances,121 but not all,9 it can reduce the incidence
of the condition.
Displacement
A variety of devices have been proposed that respond to motion or displacement. They are designed for
the adductor pollicis muscle. A thorough evaluation of these devices has not been made, but data
indicate that there are slight but clinically insignificant differences between the results such
displacement transducers and mechanomyography provide.122
Phonomyography
A contracting muscle emits low frequency sounds. Train-of-four response and fade can be heard with a
stethoscope placed over the adductor pollicis muscle. A quantitative response can be obtained with
special microphones sensitive to frequencies (2 Hz) below the threshold of the human ear. An excellent
correlation between phonomyography and force measurement has been found at several muscles,
including the adductor pollicis and the corrugator supercilii.123 At the time of writing, no commercial
devices using phonomyography were available.
Choice of Muscle
Muscles do not respond in a uniform fashion to neuromuscular blocking drugs. After administration of a
neuromuscular blocking agent, differences can be measured with respect to onset time, maximum
blockade, and duration of action. It is not practical to monitor the muscles of physiological importance,
for example, the abdominal muscles during surgery, or the respiratory and upper airway muscles
postoperatively. A better approach is to choose a monitoring site that has a response similar to the
muscle of interest. For example, monitoring the response of the facial nerve around the eye is a good
indicator of intubating conditions, and the use of the adductor pollicis muscle during recovery reflects
upper airway muscle function. Another strategy is to stick to one monitoring site, such as the adductor
pollicis muscle, and interpret the information provided from knowledge of the different responses
between muscles (Fig. 20-14).
Adductor Pollicis Muscle
The adductor pollicis muscle is accessible during most surgical procedures. It is supplied by the ulnar
nerve, which becomes superficial at the wrist where a negative electrode can be positioned. The positive
electrode is applied a few centimeters proximally (Fig. 20-12). The force of contraction of the adductor
pollicis muscle can be measured easily, and it has become a standard in research. After injection of a
dose that produces less than 100% blockade, the time to maximal blockade is longer than in centrally
located muscles.124,125 The adductor pollicis muscle is relatively sensitive to nondepolarizing
neuromuscular blocking drugs, and during recovery it is blocked more than some respiratory muscles
such as the diaphragm,124 laryngeal adductors,125 and abdominal muscles (Fig. 20-14).126 There is evidence
that recovery of the adductor pollicis and of upper airway muscles occurs more or less simultaneously
(Fig. 20-14).127
Figure 20-14. Approximate time course of twitch height after
rocuronium, 0.6 mg/kg, at different muscles. Diaphragm,
diaphragm; larynx, laryngeal adductors (vocal cords); CS,
corrugator supercilii muscle (eyebrow); Abd, abdominal
muscles; OO, orbicularis oculi muscle (eyelid); GH, geniohyoid
View Figure
muscle (upper airway); AP, adductor pollicis muscle (thumb).
(Data are taken or inferred from references 75, 126, 127, and
129.)
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The adductor pollicis muscle can also be stimulated by applying electrodes directly over it. This can be
accomplished by placing the two electrodes in the space lying between the base of the first and second
metacarpals, on the palmar and dorsal aspects on the hand, respectively (Fig. 20-12). Such a stimulation
avoids the confounding movement of hypothenar muscles. Direct muscle stimulation with this electrode
position does not normally occur because neuromuscular blocking agents abolish the response
completely.128 The ability to detect fade by visual or tactile means is the same, whether the stimulating
electrodes are applied at the wrist or the hand.115
Other Muscles of the Hand
Ulnar nerve stimulation also produces flexion and abduction of the fifth finger, which usually recovers
before the adductor pollicis muscle, the discrepancy in first twitch or train-of-four ratio being of the
order of 15 to 20%.119 Relying on the response of the fifth finger might overestimate recovery from
blockade. Abduction of the index finger also results from stimulation of the ulnar nerve because of
contraction of the first dorsal interosseous, the sensitivity of which is comparable with that of the
adductor pollicis muscle. The hypothenar eminence (near the fifth finger) and the first dorsal interosseous
are particularly well suited for EMG recordings.119 Stimulation in the hand (Fig. 20-12) eliminates
contraction of the hypothenar muscles, but may evoke movement of the first dorsal interosseous.
Muscles Surrounding the Eye
There seem to be major differences in the response of muscles innervated by the facial nerve and located
around the eye, and these differences have introduced some confusion in the literature. The orbicularis
oculi muscle essentially covers the eyelid, and its response to neuromuscular blocking agents is similar
to that of the adductor pollicis muscle.129 However, it is customary to observe the movement of the
eyebrow, and recordings at that site are similar to that of the laryngeal adductors (Fig. 20-14).129 Onset of
blockade is more rapid and recovery occurs sooner than at the adductor pollicis. Thus, facial nerve
stimulation with inspection of the response of the eyebrow (which most likely represents the effect of the
corrugator supercilii, not the orbicularis oculi muscle) is indicated to predict intubating conditions and to
monitor profound blockade. The facial nerve can be stimulated 2 to 3 cm posterior to the lateral border
of the orbit. There is no need to use stimulating currents >20 to 30 mA.
Muscles of the Foot
The posterior tibial nerve can be stimulated behind the internal malleolus to produce flexion of the big
toe by contraction of the flexor hallucis muscle. The response of this muscle is comparable with that of
the adductor pollicis muscle. Stimulation of the external peroneal nerve produces dorsiflexion, but the
sensitivity of the muscles involved has not been measured.
Clinical Applications
Monitoring Onset
The quality of intubating conditions depends chiefly on the state of relaxation of muscles of the jaw,
pharynx, larynx, and respiratory system. Onset of action is faster in all these muscles than in the hand or
foot because they are closer to the central circulation and they receive a greater blood flow. Among
these central muscles, the diaphragm and especially the laryngeal adductors are the most resistant to
nondepolarizing agents. The diaphragm is an important muscle because its blockade prevents coughing,
and if laryngeal muscles are paralyzed, vocal cords are relaxed, allowing easy passage of a tracheal tube.
The relationship between onset time in laryngeal and hand muscles depends on dose. At relatively low
doses (e.g., rocuronium, 0.3 to 0.4 mg/kg), onset time is slower at the adductor pollicis than at the
laryngeal muscles. If the dose is increased (e.g., rocuronium, 0.6 to 1.0 mg/kg), onset is faster at the
adductor pollicis muscle because these doses produce 100% blockade at the adductor pollicis without
blocking laryngeal muscles completely (Fig. 20-14).73 Onset time decreases considerably in any muscle if
the dose given is sufficient to reach 100%. Finally, if the dose is large enough to block the laryngeal
muscles completely, onset time again becomes shorter at the larynx. It is not surprising that monitoring
the adductor pollicis muscle predicts intubating conditions poorly. Facial nerve stimulation with visual
observation of the response over the eyebrow gives better results because the response of the corrugator
supercilii is close to that of the vocal cords. Train-of-four fade takes longer to develop than single-twitch
depression (Fig. 20-9), and during onset, train-of-four stimulation does not have any advantages over
single-twitch stimulation at 0.1 Hz.
Monitoring Surgical Relaxation
Adequate surgical relaxation is usually obtained when fewer than two or three visible twitches are
observed at the adductor pollicis muscle. However, this criterion might prove inadequate in certain
circumstances when profound relaxation is required owing to the discrepancy between the adductor
pollicis and other muscles. In this case, the PTC can be used at the adductor pollicis muscle,118 provided
that this type of stimulation is not repeated more often than every 2 to 3 minutes. A suitable alternative
is stimulation of the facial nerve with observation of the response over the eyebrow, which recovers at
the same rate as such resistant muscles as the diaphragm.124,129
Monitoring Recovery
Complete return of neuromuscular function should be achieved at the conclusion of surgery unless
mechanical ventilation is planned. Thus, monitoring is useful in determining whether spontaneous
recovery has progressed to a degree that allows reversal agents to be given and to assess the effect of
these agents.
The effectiveness of anticholinesterase agents depends directly on the degree of recovery present when
they are administered. Preferably, reversal agents should be given only when four twitches are visible at
the adductor pollicis muscle,130 which corresponds to a first-twitch recovery of >25%. The presence of
spontaneous breathing is not a sign of adequate neuromuscular recovery. The diaphragm recovers earlier
than the much more sensitive upper airway muscles, such as the geniohyoid, which recovers, on average,
at the same time as the adductor pollicis muscle.127 To prevent upper airway obstruction after extubation,
it is preferable to use the adductor pollicis muscle to monitor recovery, instead of the more resistant
muscles of the hypothenar eminence or those around the eye.
Finally, the adequacy of recovery should be assessed. Traditionally, a train-of-four ratio of 0.7 was
considered to be the threshold below which residual weakness of the respiratory muscles could be
present. There is abundant evidence that significant weakness may occur up to train-of-four ratio values
of 0.9.10,123 Awake volunteers given mivacurium failed to perform the head-lift test when the train-of-four
ratio at the adductor pollicis muscle decreased below 0.62, but needed a train-of-four ratio of at least
0.86 to hold a tongue depressor
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between their teeth (Fig. 20-15).131 This suggests that the head-lift test does not guarantee full recovery,
and that the upper airway muscles used to retain a tongue depressor are very sensitive to the residual
effects of neuromuscular blocking drugs. Furthermore, impairment in swallowing and laryngeal
aspiration of a pharyngeal fluid was observed at train-of-four ratios as high as 0.9 in volunteers given
vecuronium (Fig. 20-4).132
Figure 20-15. Correlation between train-of-four (TOF)
responses at the adductor pollicis muscle and certain clinical
tests of neuromuscular recovery. Volunteers were given
mivacurium and were asked to lift their heads for 5 seconds
(head lift), lift their legs for 5 seconds (leg lift), or hold a
tongue depressor between their teeth against force (tongue
depressor). The minimum TOF ratio (and SD) when each of
these tests was passed is indicated. (Data from Kopman et
View Figure
al.131)
Anesthetized patients appear considerably more sensitive to the ventilatory effects of neuromuscular
blocking drugs than are awake patients. Whereas tidal volume and end-tidal CO2 are preserved in awake
patients receiving relatively high doses of neuromuscular blocking drugs,133 anesthetized adults have a
decreased tidal volume and increased PCO2 with doses of pancuronium as low as 0.5 mg.134 In conscious
volunteers, administration of small doses of vecuronium to maintain train-of-four at <0.9 leads to severe
impairment of the ventilatory response to hypoxia (Fig. 20-16).135 The response to hypercapnia is
maintained, and this indicates that the response to hypoxia is not a result of respiratory muscle
weakness.135
Taken together, the results of these investigations indicate that normal respiratory and upper airway
function does not return to normal unless the train-of-four ratio at the adductor pollicis muscle is 0.9 or
more. However, it has become apparent that human senses fail to detect either a train-of-four or 50-Hz
tetanic fade when the train-of-four ratio is as low as 0.3.115 With double-burst stimulation, detection
failures may occur at train-of-four ratios of 0.6 to 0.7.115 Compared with the train-of-four, the ability to
detect fade is not improved by using tetanic stimulation at 50 Hz for 5 seconds. However, fade can be
detected visually at train-of-four ratios of 0.8 to 0.9 by using 100-Hz tetanic stimulation,46,115 although this
threshold may vary from patient to patient.115 Because of the presence of posttetanic facilitation, 50- or
100-Hz stimuli should not be applied more often than every 2 minutes. Because of the limitations of one's
senses, it has been advocated that quantitative assessment of the train-of-four ratio be made routinely.10
Mechanographic and EMG equipment give reliable values of train-of-four ratio, but the use of this
equipment is limited by size, cost, and convenience. Accelerometers are less bulky and cheaper, but they
can overestimate the value of train-of-four ratio during recovery.116 It has been suggested that a train-offour ratio of 1.0 obtained by accelerometry must be obtained before neuromuscular function can be
considered complete.115 Monitoring devices based on the measurement of displacement or sound may
prove to have more reliable train-of-four ratios than accelerometry. In one study, a transmission module
sensitive to bending and deformation was found to yield train-of-four ratio values comparable to
mechanomyography during the recovery period.122
Figure 20-16. Response to hypoxia is impaired during recovery
from vecuronium blockade. Normal response is an increase in
minute volume (MV) or tidal volume (TV; control). These
increases are decreased significantly when vecuronium
produces a train-of-four ratio (TOF) of 0.7 at the adductor
pollicis muscle. They return to near-normal values at a TOF
View Figure
>0.9. (Data from Eriksson et al.135)
In response to the shortcomings of visual or tactile evaluations, another approach to recovery is to wait
until sufficient spontaneous recovery is present and give reversal agents systematically. If given at a
train-of-four count of 2 during cisatracurium or rocuronium blockade, complete recovery is not achieved
until 15 minutes or so later, with some patients still having train-of-four ratios <0.9 after 30 minutes.136
Thus, the recommendation is to wait until all four twitches have reappeared. In any event, clinicians must
be aware of the limitations of the tests they are using and complete their evaluations with clinical tests.
Factors Affecting the Monitoring of Neuromuscular Blockade
Many drugs interfere with neuromuscular function and these are dealt with elsewhere (see “Drug
Interactions”). However, certain situations make the interpretation of data on neuromuscular function
difficult. Central hypothermia may slow the metabolism of neuromuscular blocking agents and prolong
blockade in all muscles of the body.137 If the extremity where monitoring is performed is cold, the degree
of block will be accentuated. Thus, if only the monitored hand is cold, without central hypothermia, the
degree of paralysis will appear to be increased.137 Resistance to nondepolarizing neuromuscular blocking
drugs occurs with nerve damage, including peripheral nerve trauma, cord transection, and stroke. In this
case, monitoring of the involved limb would tend to underestimate the degree of muscle paralysis. The
level of paralysis should also be adjusted for the type of patient, as well as the type of surgery. For
example, it is not necessary to paralyze frail individuals or patients at the extremes of age to the same
extent as young muscular adults. The same applies to patients with debilitating muscular diseases.
Neuromuscular monitoring by itself does not guarantee adequate relaxation during surgery and complete
recovery postoperatively. The surgical field may be poor in spite of full paralysis of the hand because of
difference in response between muscles. For example, evidence of breathing efforts can be manifest on
the expired CO2 curve when no twitch is present at the adductor pollicis muscle following ulnar
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nerve stimulation, reflecting the earlier recovery of the diaphragm.124,126 Residual paralysis might occur
because of excess neuromuscular blocking agents given, early administration of reversal, or an abnormal
response of the patient. The effect of the neuromuscular blocking drug is the same whether or not
monitoring is used. Neuromuscular monitoring can help in the diagnosis of inadequate skeletal muscle
relaxation during surgery or insufficient recovery after surgery, but does not, in itself, treat these
conditions.9
Antagonism of Neuromuscular Block
In most circumstances, all efforts should be made to ensure that the patient leaves the operating room
with unimpaired muscle strength. Specifically, respiratory and upper airway muscles must function
normally so the patient can breathe, cough, swallow secretions, and keep his or her airway patent. Two
strategies can be adopted to achieve this goal. The first is to titrate neuromuscular blocking agents
carefully so that no residual effect is manifest at the end of surgery. The second is to accelerate recovery
by giving a reversal drug. This second option is probably safer, but both strategies require careful
assessment of blockade. A third possibility that might be available in the near future is selective binding
of neuromuscular blocking agents with a cyclodextrin molecule to restore neuromuscular function.
Assessment of Neuromuscular Blockade
Spontaneous breathing can resume even if relatively deep degrees of paralysis are still present because of
the relative diaphragm-sparing effect of neuromuscular blocking agents. Spontaneous ventilation,
adequate to prevent hypercapnia, can be maintained despite considerable measurable skeletal muscle
weakness if a patent airway is ensured. The ability to perform maneuvers such as vital capacity,
maximum voluntary ventilation, and forced expiratory flow rate recovers at less intense levels of paralysis
because it requires a greater strength.133 However, such tests are difficult to perform in everyday
practice, particularly when the patient is recovering from general anesthesia. Moreover, the weakest
point in the respiratory system is the upper airway. When given vecuronium, swallowing was impaired and
laryngeal aspiration occurred when the train-of-four ratio was ≤0.9.132 These problems are difficult to
diagnose when a tracheal tube is in place. Consequently, several indirect indices, which are easier to
measure, have been correlated with the more specific tests of lung and upper airway function.
Clinical Evaluation
Several crude tests have been suggested, including head lift for 5 seconds, tongue protrusion, and the
ability to lift the legs off the bed to determine recovery of neuromuscular function. Pavlin et al.133
correlated the maximum inspiratory pressure with tests of skeletal muscle strength and of airway
musculature in conscious volunteers receiving d-tubocurarine. As the dose was increased, head lift and
leg raising were affected first. Then, the ability to swallow, touch teeth, and maintain a patent airway
was impaired. At that time, hand grip strength was decreased markedly. Nevertheless, as long as the
mandible was elevated by an observer, end-tidal CO2 was normal even when the subject failed all other
tests. From these data, Eriksson et al.132 concluded that ability to maintain head lift for 5 seconds usually
indicates sufficient strength to protect the airway and support ventilation. However, Kopman et al.131
have shown, in volunteers, that the most sensitive test is the ability to clamp the jaws shut and prevent
removal of a tongue depressor. This maneuver correlated with a train-of-four ratio measured at the
adductor pollicis muscle of >0.86, whereas head lift and leg lift could be performed at more intense levels
of paralysis (train-of-four approximately 0.6; Fig. 20-15). All subjects complained of visual symptoms until
train-of-four was >0.9. Pressure measurements in the upper esophagus have been shown to be decreased
(Fig. 20-4) and laryngeal aspiration detected at a train-of-four ratio <0.9.132 Thus, it appears that a normal
head lift or leg lift is insufficient to guarantee normal upper airway function. The ability to resist removal
of an object (such as a tongue depressor or a tracheal tube) from the mouth by closing the teeth probably
correlates better with adequate upper airway function.
Evoked Responses to Nerve Stimulation
The clinical tests previously described are usually unobtainable in the patient recovering from anesthesia.
Furthermore, it is preferable to assess the degree of recovery before emergence. Evoked responses to
nerve stimulation are then appropriate. The target is a train-of-four >0.9, considering that upper airway
function does not recover completely until the train-of-four ratio at the adductor pollicis muscle is at
least 0.9.
With the introduction of short- and intermediate-duration nondepolarizing agents into clinical practice,
the use of reversal agents has been considered by some as optional. The decision to omit pharmacologic
reversal of neuromuscular blockade must be made carefully because the presence of residual paralysis
may be missed. As mentioned earlier, manual and tactile evaluation of neuromuscular blockade by trainof-four or 50-Hz tetanic stimulation may fail to detect fade.115 Double-burst stimulation is more sensitive,
but becomes unreliable at train-of-four ratios in the range of 0.6 to 0.9.115 The most sensitive test is the
ability to maintain sustained contraction to 100-Hz tetanus for 5 seconds. Fade may be detected when
train-of-four ratio is as high as 0.8 to 0.9.46,115 Tetanic stimulation at 100 Hz is painful and must be
performed only in adequately anesthetized patients.
Because of the limitations of the visual and tactile estimate of the train-of-four response during recovery,
objective measurement has been advocated.10 Acceleromyographic recordings might be the most practical
because accelerometers are cheap and easy to use. However, it must be appreciated that the train-offour ratio obtained with accelerometry is greater than that measured with mechanomyography and may
exceed 1.0. An accelerographic train-of-four ratio of 1.0 has been proposed as the equivalent of a
mechanomyographic train-of-four of 0.9.115
Residual Paralysis
Several studies have demonstrated that residual neuromuscular blockade is frequent in patients in the
recovery room after surgery. Viby-Mogensen et al.138 found in 72 adult patients given long-acting agents
that the train-of-four ratio was 0.7 in 30 (42%) patients, and that 16 of the 68 patients (24%) who were
awake were unable to sustain head lift for 5 seconds. In that study, the patients received appropriate
doses of neostigmine. Similar results have been obtained in other parts of the world (Table 20-1).9,139 The
incidence of train-of-four ratio 0.7 is reduced from about 30% to <10% if the intermediate agents
atracurium or vecuronium are substituted for the long-acting drugs and if reversal is given.9,139,140 However,
the actual incidence of residual paralysis was certainly underestimated in the earlier studies because of
the criterion used (train-of-four ratio of 0.7).
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Recently, there has been a trend for a greater incidence of residual paralysis, even with intermediateduration drugs. This can be explained by two factors. The threshold for residual paralysis has been raised
from a train-of-four ratio of 0.7 to 0.8 and then to 0.9.9 However, the most important reason for high
incidence of residual paralysis seems to be omission of reversal. In one study, more systematic institution
of pharmacologic reversal was associated with a decrease in the incidence of residual paralysis (train-offour >0.9) from 62% to 3%.141
Clinical Importance
Residual paralysis in the recovery room has been shown to be associated with significant morbidity. In
1997, Berg et al.140 studied nearly 700 general surgical patients who randomly received pancuronium,
vecuronium, or atracurium to produce surgical relaxation. In patients who had received pancuronium, the
incidence of postoperative partial paralysis, defined by the then-accepted criterion of a train-of-four
ratio <0.7, was 5 times that in patients receiving either of the two intermediate-acting drugs (26 vs. 5%).
In addition, the incidence of atelectasis demonstrated on chest radiographs taken 2 days later was greater
in patients who had received pancuronium and who had not attained a train-of-four ratio of 0.7 (16%)
than in those who exceeded this threshold (4.8%).140 Intense residual block has been demonstrated in
patients after cardiac surgery, especially if pancuronium was chosen over rocuronium.66
Reversal Agents
So far, the only compounds that have been widely used to reverse the effect of neuromuscular blocking
agents are the anticholinesterase drugs. The pharmacologic principle involved is inhibition of
acetylcholine breakdown to increase its concentration of acetylcholine at the neuromuscular junction,
thus tilting the competition for receptors in favor of the neurotransmitter.139 Other drugs such as suramin
and 3–4 aminopyridine are not as effective, or more toxic, or both. The monopoly occupied by
anticholinesterase agents might be challenged soon with the introduction of a selective binding agent,
sugammadex, which is now undergoing clinical trials in North America and Europe.
Anticholinesterases: Mechanism of Action
Neostigmine, edrophonium, and pyridostigmine inhibit acetylcholinesterase, but this may not be the only
mechanism by which blockade is antagonized. This inhibition is present at all cholinergic synapses in the
peripheral nervous system. Thus, the anticholinesterases have potent parasympathomimetic activity,
which is attenuated or abolished by the administration of an antimuscarinic agent, atropine or
glycopyrrolate. Neostigmine, edrophonium, and pyridostigmine are quaternary ammonium compounds,
which do not penetrate the blood–brain barrier well. Thus, although these agents have the ability to
affect cholinergic function in the central nervous system, the concentrations in the brain are usually too
small for such an effect. Physostigmine is an anticholinesterase that can cross the blood–brain barrier
easily. For this reason, it is not used to reverse neuromuscular blockade.
Neostigmine and pyridostigmine are attached to the anionic and esteratic sites of the
acetylcholinesterase molecule and produce longer lasting inhibition than edrophonium. Neostigmine and
pyridostigmine are inactivated by the interaction with the enzyme, whereas edrophonium is unaffected.139
Inhibition of acetylcholinesterase results in an increased amount of acetylcholine reaching the receptor
and in a longer time for acetylcholine to remain in the synaptic cleft. This causes an increase in the size
and duration of the end plate potentials.142 There is evidence that some of the effects of neostigmine are
not the result of cholinesterase inhibition.142
Anticholinesterases also have presynaptic effects. In the absence of neuromuscular blocking drugs, they
potentiate the normal twitch response in a way similar to succinylcholine, probably as a result of the
generation of action potentials that spread antidromically. A ceiling effect, that is, the inability for large
doses to produce an increasing effect, has been demonstrated in vitro143 and can be observed in
patients.144
Neostigmine Block
Large doses of anticholinesterases, especially if given when neuromuscular block is absent, may produce
evidence of neuromuscular dysfunction. For example, dose-dependent decreases in the EMG activity of
the genioglossus and the diaphragm have been measured following neostigmine administration in rats.145
The problem might be less when some degree of neuromuscular blockade is present before neostigmine
is given. The mechanism involved is uncertain. There are no clinical reports of postoperative weakness
attributed to reversal agents. Still, it appears prudent to reduce the dose of anticholinesterase agent if
recovery from neuromuscular block is almost complete.
Potency
Dose-response curves have been constructed for edrophonium, neostigmine, and pyridostigmine. During a
constant infusion of neuromuscular blocking drugs, the curves are obtained by plotting the peak effect
versus the dose of reversal agent. In this situation, neostigmine was found to be approximately 12 times
as potent as edrophonium.146 However, the curves are not parallel, that of edrophonium being flatter. This
indicates that edrophonium is effective over a narrower range of blockade and less effective against deep
blockade. This was verified when neostigmine and edrophonium were used to reverse atracurium
blockade. More neostigmine and edrophonium were required to reverse deep (99%) than moderate (90%)
block, but the difference was greater for edrophonium.147 There is no difference in the dose-response
relationship of anticholinesterases if vecuronium is infused instead of pancuronium, but there is a marked
shift to the left for the curves obtained during vecuronium block if the reversal agent is given during
spontaneous recovery.148 This indicates that anticholinesterase-assisted recovery is the sum of two
components: (1) spontaneous recovery from the neuromuscular blocking agent itself, which depends on
the pharmacokinetic characteristics of the drug, and (2) assisted recovery, which is a function of the dose
and type of anticholinesterase agent given.
Pharmacokinetics
Following bolus intravenous injection, the plasma concentration of the anticholinesterases decreases
rapidly during the first 5 to 10 minutes and then more slowly.139 Volumes of distribution are in the range of
0.7 to 1.4 L/kg and the elimination half-life is 60 to 120 minutes. The drugs are water-soluble, ionized
compounds so that their principal route of excretion is the kidney. Their clearances are in the range of 8
to 16 mL/kg/min, which is much greater than the glomerular filtration rate because they are actively
secreted into the tubular lumen. Their clearance is reduced markedly in patients in renal failure.
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Figure 20-17. Reversal of pancuronium blockade at 10% twitch
recovery. Reversal is given at time zero. Edrophonium is faster then
neostigmine, which is faster than pyridostigmine. (Redrawn from
Ferguson A, Egerszegi P, Bevan DR: Neostigmine, pyridostigmine, and
edrophonium as antagonists of pancuronium. Anesthesiology 1980; 53:
390.)
View Figure
Pharmacodynamics
The onset of action of edrophonium (1 to 2 minutes) to peak effect is much more rapid than that of
neostigmine (7 to 11 minutes) or pyridostigmine (15 to 20 minutes; Fig. 20-17).162 The reason for the
differences is uncertain, but may be related to the different rates of binding to the enzyme. The duration
of action (1 to 2 hours) is similar to their elimination half-life. Even when used to reverse blockade
produced by long-acting agents, duration of action of anticholinesterase agents is comparable with or
most often exceeds that of the neuromuscular blocking drug. Well-documented recurarization has not
been reported. In practice, cases of apparent reparalysis in the recovery room are incomplete reversal
that was initially thought to be complete. Either manual or visual assessment is performed using the trainof-four or tetanus mode, which can yield to gross underevaluation of residual paralysis, or respiratory
function appeared adequate when the tracheal tube is in place, but once extubated, the patient cannot
maintain a patent airway.
Factors Affecting Reversal
Several factors modify the rate of recovery of neuromuscular activity after reversal.
Intensity of Block
The more intense the block at the time of reversal, the longer the recovery of neuromuscular activity
(Fig. 20-18).144 In addition, neostigmine is more effective than edrophonium or pyridostigmine in
antagonizing intense (90%) blockade. When reversal is administered after spontaneous recovery to ≥25% T1
has occurred, recovery is rapid and the time from reversal to train-of-four >0.9 is usually only a few
minutes, although recovery after pancuronium may not be complete.68 Thus, Kopman et al.136
recommended that reversal should not be attempted until T1 ≥25% when four twitches to train-of-four
stimulation are visible. Attempted reversal at only two twitches may take 30 minutes or more to reach
train-of-four of 0.9.
Figure 20-18. Neostigmine is more effective at greater degree
of recovery from rocuronium blockade. Time to reach a trainof-four ratio of 0.8 after various doses of neostigmine. This
time is less if neostigmine is given at 25% than at 10% firsttwitch recovery. Notice a ceiling effect for neostigmine at
doses >0.035 mg/kg. A dose of 0 indicates no reversal given.
(Data from McCourt et al.144)
View Figure
One might argue that reversal can be attempted earlier, for instance when there is only one or no twitch
visible following train-of-four stimulation, because one would otherwise spend time waiting for all four
twitches to reappear. Several studies dealt with the problem of total time between injection of the
neuromuscular blocking agent until complete recovery, with the reversal agent given at different levels
of spontaneous recovery. Bevan et al.148 administered large doses of neostigmine (0.07 mg/kg) after
rocuronium and vecuronium and measured time until train-of-four ratio was 0.9. Neostigmine decreased
the time to recovery, no matter when it was given. However, time from injection to full reversal was not
less when neostigmine was given 5 minutes after rocuronium (42.1 minutes) than at 25% recovery (28.2
minutes; Fig. 20-19).148 In addition, giving the reversal agent too early leads to a period of “blind
paralysis” because neostigmine-assisted recovery is characterized by an early, rapid phase, followed by
slower recovery. As a result, the interval between a train-of-four ratio of 0.4 to 0.9, that is, the time
when fade is difficult to detect, is likely to be much longer with early neostigmine administration. Thus,
there is little advantage in attempting early reversal.
Dose
Over a certain dose range, the degree and rate of reversal depends directly on dose.144,147 However, all
anticholinesterase agents demonstrate a ceiling effect (Fig. 20-18). Usually, there is no added benefit in
giving doses exceeding 0.07 mg/kg neostigmine, or 1.0 mg/kg edrophonium.
Choice of Neuromuscular Blocking Agent
Recovery of neuromuscular activity after reversal depends on the rate of spontaneous recovery as well as
the acceleration induced by the reversal agent. Consequently, the overall recovery of intermediate-acting
agents (atracurium, vecuronium, mivacurium, rocuronium) following the same dose of anticholinesterase
is more rapid and more complete than after pancuronium,
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d-tubocurarine, or gallamine.68 This difference is probably why residual paralysis is more frequent with
longer-acting neuromuscular blocking agents. After prolonged infusions, recovery is slower than after
intermittent bolus administration.
Figure 20-19. Time from injection of rocuronium until
recovery to train-of-four ratio (TOF) of 0.9 in adults. Reversal
with neostigmine was either not given (Spont) or given at 25%,
10%, or 1% twitch recovery, or given 5 minutes after
rocuronium, when there was no twitch. Times from rocuronium
injection to 1% first twitch, 25% first twitch, and TOF of 0.9
are indicated. Neostigmine was optimal when given at 10 to
View Figure
25%. Giving it early had no advantage. (Data from Bevan et
al.148)
Age
Recovery of neuromuscular activity occurs more rapidly with smaller doses of anticholinesterases in
infants and children than in adults (Fig. 20-20).148 Residual weakness in the recovery room is found less
frequently in children than in adults. The effectiveness of reversal has not been studied extensively in the
elderly. Although the elimination of anticholinesterases is reduced in this age group, this reduction is
counterbalanced by the tendency for neuromuscular blockade to wear off more slowly. This is especially
true of steroidal neuromuscular blocking agents, such as vecuronium and rocuronium, which have a
slower recovery index in the elderly.
Figure 20-20. Same graph as in Figure 20-19, but in children 2
to 12 years old. Spontaneous recovery from rocuronium
blockade (Spont) is more rapid, as well as neostigmine-assisted
recovery. (Data from Bevan et al.148)
View Figure
Drug Interactions
Drugs that potentiate neuromuscular blockade can slow reversal or produce recurarization if given after
anticholinesterase administration. Halogenated agents, when continued after neostigmine administration,
prolong time to full reversal. Even when they are discontinued at the time of anticholinesterase drug
administration, reversal time is not reduced significantly, probably because washout of the vapor from
muscle tissue takes time. Care must be taken if aminoglycoside antibiotics or magnesium must be given
shortly after reversal agents.
Renal Failure
Anticholinesterases are actively secreted into the tubular lumen so that their clearance is reduced in
renal failure.139 Thus, duration of action of neostigmine and edrophonium is increased in renal failure, at
least to a comparable extent as duration of action of the neuromuscular blocking agent. No cases of
recurarization have been reported.
Anticholinesterases: Other Effects
Cardiovascular
Anticholinesterases provoke profound vagal stimulation. The time course of the vagal effects parallels the
reversal of block, which is rapid for edrophonium and slower for neostigmine. However, the bradycardia
and bradyarrhythmias can be prevented with anticholinergic agents. Atropine has a rapid onset of action
(1 minute), duration of 30 to 60 minutes, and crosses the blood–brain barrier. Its time course makes it
appropriate for use in combination with edrophonium,146 whereas glycopyrrolate (onset 2 to 3 minutes) is
more suitable with neostigmine or pyridostigmine. Because glycopyrrolate does not cross the blood–brain
barrier, it is believed that the incidence of memory deficits after anesthesia is less than that after
atropine. If atropine is given with neostigmine, the dose is approximately half that of neostigmine
(atropine 20 µg/kg for neostigmine 40 µg/kg). Such a combination leads to an initial tachycardia followed
by a slight bradycardia. With glycopyrrolate, the dose is one-fourth to one-fifth that of neostigmine.
Atropine requirements are less with edrophonium than with neostigmine (atropine 7 to 10 µg/kg with
edrophonium 0.5 mg/kg).
Other Cholinergic Effects
Anticholinesterases produce increased salivation and bowel motility. Although atropine blocks the former,
it appears to have little effect on peristalsis. Some reports claim an increase in bowel anastomotic
leakage after the reversal of neuromuscular blockade. There has been concern over the possible impact
of anticholinesterase agents on postoperative nausea and vomiting (PONV). A meta-analysis, published in
1999, concluded that neostigmine had no effect on the overall incidence of PONV, but large doses (2.5 mg
or more in adults) was associated with a higher incidence of PONV than no reversal, while lower doses led
to less PONV.149 A more recent meta-analysis reanalyzed the data and incorporated additional studies. It
concluded that there was no relation between administration
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of neostigmine and PONV.150 At any rate, possible nausea and vomiting is preferable to signs and symptoms
of respiratory paralysis.
Respiratory Effects
Anticholinesterases may cause an increase in airway resistance, but anticholinergics reduce this effect.
Several other factors, such as pain, the presence of an endotracheal tube, or light anesthesia, may
predispose to bronchoconstriction at the end of surgery so that it is difficult to incriminate the reversal
agents.
Clinical Use
Several strategies have been proposed to restore neuromuscular function at the end of surgery and
anesthesia. One of them involves restricting the dose of nondepolarizing blocking agent at induction of
anesthesia to what is necessary for the duration of the procedure, minimal additional doses and reliance
of complete spontaneous recovery in an attempt to avoid reversal with anticholinesterase agents. This
approach is not without dangers. Even relatively modest doses (2 × ED95) of atracurium, vecuronium, or
rocuronium are associated with residual paralysis (train-of-four ratio <0.9) after as long as 4 hours after
injection.120 Visual or tactile monitoring with train-of-four, 50 Hz-tetanus, or double-burst stimulation
stimulation cannot rule out some degree of residual paralysis.115 Only a sustained response to a 100-Hz
tetanus may rule out the presence of residual paralysis by tactile or visual means.44,115 The use of objective
monitoring, such as acceleromyography, is even better.115 Still, pharmacologically assisted recovery is
expected in most cases, as it is illusory to aim for complete recovery only by careful titration of
neuromuscular blocking agents. In a study examining anesthetic outcomes in The Netherlands, the use of
reversal agents was found to be associated with a tenfold reduction in mortality.151 Not surprisingly, the
more systematic use of reversal agents in one institution led to a substantial decrease in residual
paralysis.141
Administration of anticholinesterase agents will accelerate recovery, no matter when they are given in
the course of recovery (Fig. 20-19). However, there are advantages in giving reversal agents when
spontaneous recovery is well under way, preferably when four twitches are present after train-of-four
stimulation. If neostigmine is given when deep blockade is present (no twitch or only one twitch present;
Figs. 20-18 and 20-19), reversal takes longer than if four twitches are present. As a result, time from
injection of rocuronium until full recovery (train-of-four >0.9) is not reduced, and my in fact be
increased, if neostigmine is given too early (Fig. 20-19). Furthermore, the patient might be more difficult
to manage with early reversal: duration of blind paralysis (from train-of-four of 0.4, when train-of-four
fade becomes undetectable, until train-of-four is 0.9) is longer with early reversal. This means that
missing residual paralysis is more likely with hasty administration of anticholinesterase agents. Therefore,
if four twitches are not visible after train-of-four stimulation, it is recommended to keep the patient
anesthetized and mechanically ventilated until four twitches reappear and then administer
anticholinesterases.
Intense blockade is not expected to be reversed effectively by increasing the dose of anticholinesterase
(Fig. 20-18). In general, neostigmine doses of 0.04 to 0.05 mg/kg should be sufficient, and there is no
advantage in exceeding 0.07 mg/kg because of the ceiling effect of the drug. Edrophonium is not
recommended for intense block. Pyridostigmine has a slow onset of action and does not appear to
accelerate reversal of short- and intermediate-duration drugs to a great extent.
When recovery appears almost complete—that is, when four seemingly equal twitches are seen after
train-of-four stimulation—a reduced dose of neostigmine (0.015 to 0.02 mg) is probably adequate. In this
situation, edrophonium (0.2 to 0.5 mg/kg) may also be given, with the added advantage of rapid recovery
(2 minutes). Either drug is preferable to no reversal at all because they reduce the duration of blind
paralysis.
Sugammadex
A new method of reversing neuromuscular blockade might be available in the near future. Sugammadex,
previously called ORG 25969, leads to restoration of normal neuromuscular function not by interfering
with acetylcholine, the nicotinic receptor or acetylcholinesterase, but by selectively binding to
rocuronium, and to a lesser extent to vecuronium and pancuronium.152 The compound is a cyclodextrin,
made up of eight sugars arranged in a ring to make a center to accommodate the rocuronium molecule.
Once bound, rocuronium is held in place by polar side chains attached to the ring. Because sugammadex
does not bind to any known receptor, it is devoid of major cardiovascular or other side effects. It does not
bind neuromuscular blocking drugs that do not have a steroid nucleus. The benzylisoquinolines, such as
atracurium, cisatracurium and mivacurium, and succinylcholine are unaffected by sugammadex.
Mechanism of Action
Sugammadex has a molecular weight of 2,178 Daltons152 and binds with rocuronium in a 1:1 molar ratio.
The rocuronium molecule is less bulky (610 Daltons), so 3.6 mg (or mg/kg) of sugammadex is required to
bind 1.0 mg (or mg/kg) of rocuronium. Binding is tight, but not irreversible. This means that rocuronium–
sugammadex complexes form while some others break up into their two constituents. The dissociation
constant has been estimated to be 0.1 µM,152 and it is not known whether it is affected by pH,
temperature, type of fluid or tissue, or other factors. After injection of sugammadex, evidence suggests
that binding of rocuronium to sugammadex in plasma leads to a marked decrease in free (unbound)
rocuronium concentration,153 leading to the establishment of a concentration gradient of rocuronium
between the neuromuscular junction and plasma. This favors movement of rocuronium from
neuromuscular junction to plasma, producing less neuromuscular block. Vecuronium has less affinity for
sugammadex than rocuronium does, and pancuronium has less still.
Pharmacology
In patients receiving rocuronium, return of train-of-four ratio to 0.9 is accelerated by sugammadex in a
dose-dependent manner. If sugammadex is given on return of the second twitch in the train-of-four, doses
of 2 to 4 mg/kg result in the return of train-of-four ratio to 0.9 within approximately 2 minutes.154 This
interval is shorter than after either neostigmine or edrophonium reversal, when given at approximately
the same level of recovery. With lower doses (0.5 to 1 mg/kg) recovery time is longer154 and reparalysis
may be observed.155 Experience with vecuronium is limited, but studies suggest that approximately the
same, or perhaps higher, doses of sugammadex are required for the same effect.154
Sugammadex is also effective when blockade is deep, but larger doses are required (Fig. 20-21). When a
PTC of 2 is present, which for rocuronium occurs 15 to 20 minutes before return of twitch, the required
dose is probably 4 to 8 mg/kg.156
P.527
Sugammadex could also be used in the case of a failed intubation. If rocuronium 0.6 mg/kg was given,
sugammadex 8 mg/kg might be effective as early as 3 minutes after rocuronium injection, and if the dose
of rocuronium is doubled to 1.2 mg/kg, one might need 16 mg/kg of sugammadex.157 The availability of
sugammadex might make succinylcholine obsolete for intubation.152
Figure 20-21. Relationship between time to achieve a train-offour ratio of 0.9 and dose of sugammadex at moderate
(spontaneous recovery to T2 or two visible twitches) or
profound (posttetanic count [PTC] of 2). Dose of sugammadex
View Figure
required is greater with profound blockade. *No data available
for moderate blockade. (Data from references 153, 154, and
156.)
Pharmacokinetics
Sugammadex has a volume of distribution that is similar to ECF (13 L). Its terminal half-life is
approximately 2 hours.158 Both sugammadex and sugammadex–rocuronium complexes are excreted
unchanged via the kidney. No data are available in renal-failure patients. In patients receiving
rocuronium, injection of sugammadex increases the total (free plus bound) plasma concentrations of
rocuronium, which suggests that it causes sequestration of rocuronium in the plasma by drawing it from
peripheral tissues.
Clinical Use
At the time of writing (end of 2007), sugammadex had not been approved for clinical use anywhere in the
world. Not all clinical data had been published, so the following comments should be taken with caution.
Although administration of doses as high as 40 mg/kg have been reported as safe, it appears prudent to
use the lowest effective dose, to keep costs down and because safety of high doses will be established
only after use is widespread. Because the effective dose depends on the depth of blockade, monitoring is
recommended, if not essential. For reversal of rocuronium blockade when spontaneous recovery has
already started (two to four twitches present), sugammadex 2 to 4 mg/kg will produce faster recovery
than neostigmine would, without cardiovascular side effects.154 When recovery is even greater (four
apparently equal twitches), 0.5 to 1 mg/kg might be sufficient, but more data are needed on this.
The usefulness of sugammadex might be even greater in cases of deep blockade, when no twitch is seen
after train-of-four stimulation. The use of the PTC mode of stimulation will probably be useful in
establishing the dose, but if any PTC count is present, it is expected that 4 to 8 mg/kg will be required.156
The dose will be doubled in cases of deeper blockade (no PTC count) or rescue after failed intubation. It
is expected that as confidence in the efficacy of sugammadex in the context of profound blockade builds
up, clinicians might have a tendency to give larger doses of rocuronium. This change in practice could
yield some benefits. More profound relaxation provides better and faster intubating conditions, better
surgical conditions, and less damage to the laryngeal structures. Faster and more predictable recovery
could diminish the incidence of residual paralysis and reduce turn-around time. But these benefits will
come at a cost. Of course, it will be more expensive to establish muscle relaxation if the dose of
rocuronium is increased, and the cost of reversal will undoubtedly be substantial, especially if large doses
are given consistently. In addition, however, all movement will be abolished during surgery, so an
important sign of inadequate analgesia and anesthesia will be lost. It is unclear whether awareness can be
totally avoided by the use of BIS monitoring, as large doses of neuromuscular blocking agents can
depress BIS in certain circumstances.5 Finally, many foreseeable problems regarding sugammadex have
not been addressed, such as its use in renal-failure patients, the management of a patient who has
recently received sugammadex who needs surgery (for re-exploration for instance), the interaction with
steroid-type drugs or naturally occurring molecules, and the potential for bypassing the postanesthesia
care unit. Future experience with this new agent will be critical.
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